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The Role of NMDA Receptors in Alzheimer’s Disease

Jinping Liu, Lirong Chang, Yizhi Song and 2 more

Frontiers in Neuroscience · 2019 · Review · CC BY

doi:10.3389/fnins.2019.00043

Abstract

In Alzheimer's disease (AD), early synaptic dysfunction is associated with the increased oligomeric amyloid-beta peptide, which causes NMDAR-dependent synaptic depression and spine elimination. Memantine, low-affinity NMDAR channel blocker, has been used in the treatment of moderate to severe AD. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between NMDARs dysfunction and AD. This review focuses on not only changes in expression of different NMDAR subunits, but also some unconventional modes of NMDAR action.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Clinically, this disorder is characterized by global cognitive dysfunction, especially memory loss, behavior and personality changes. AD progression has been associated with a gradual damage in function and structure in the hippocampus and neocortex, the vulnerable brain areas used for memory and cognition. The neuropathologic hallmarks of AD include extracellular amyloid plaques, being composed of the amyloid beta (Aβ) peptide and intraneuronal neurofibrillary tangles (NFTs), consisting of abnormally hyperphosphorylated tau protein. Nevertheless, damage and destruction of synapses seem to better correlate with memory loss than histopathologic markers. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death.

Synaptic dysfunction may be due to perturbed synaptic Ca2+ handling in response to over activation of glutamate receptors, namely, the N-methyl-D-aspartate receptors (NMDARs). Glutamate is the primary excitatory neurotransmitter in the brain, acting at ionotropic and metabotropic glutamate receptors. Ionotropic glutamate receptors (iGluRs), responsible for fast neuronal communication at excitatory synapses, comprise three subfamilies: α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors, kainate receptors, and NMDARs. However, excessive stimulation of glutamatergic signaling results in excitotoxicity. Besides acute effects, many studies indicate a role for glutamate excitotoxicity in delayed slowly evolving neurodegeneration. The toxicity is principally mediated by excessive Ca2+ entry, primarily through NMDARs, since NMDARs have a much higher permeability for calcium ions compared to other iGluRs.

N-methyl-D-aspartate receptor plays a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory, which is not only central to the development and function of the nervous system, but also to neurotoxicity. NMDAR activation has been recently implicated in AD related to synaptic dysfunction. The pathological level of Ca2+ signaling leads to gradual loss of synaptic function and ultimate neuronal cell death, which correlates clinically with the progressive decline in cognition/memory and the development of pathological neural anatomy seen in AD patients. And this, in turn, rationalizes the clinical trial of memantine, an NMDAR antagonist, as a symptomatological and neuroprotective treatment for AD. Memantine, a non-competitive NMDA receptor antagonist, is approved for use in moderate to severe AD. It has been widely prescribed to provide symptomatic relief and enhance life quality in AD, even if it did not improve excessive agitation, and hippocampal or total brain atrophy. However, in the brain areas mainly affected in AD, NMDARs are mainly composed by GluN2A and GluN2B subunits. Furthermore, taking into account the fact that extrasynaptic GluN2B-containing NMDARs have been associated with excitotoxicity in AD, the use of a selective GluN2B subunit antagonists might be an interesting strategy to prevent synaptic dysfunction in AD.

NMDA Receptors

N-methyl-D-aspartate receptor is a ligand of glutamate, which is the primary excitatory neurotransmitter in the human brain. Most NMDAR subtypes are unique in that their opening requires the coincidence of both presynaptic glutamate release and a strong postsynaptic membrane depolarization to relieve Mg2+ block of the channel. NMDARs are permeable to Na+, K+, and high permeability to Ca2+, which acts as a second messenger to modify synapses. NMDARs are essential mediators of brain plasticity and are capable of converting specific patterns of neuronal activity into long-term changes in synapse structure and function that are thought to underlie higher cognitive functions. Activation of NMDARs leads to cytosolic free intracellular calcium ([Ca2+]i) increase, required for long-term potentiation (LTP) and long-term depression (LTD), and, more generally, for synaptic plasticity. NMDARs are also thought to be involved in a process called excitotoxicity. Abnormal NMDAR activity is associated with seizure, ischemic stroke, and neurodegenerative disorders, such as Alzheimer’s, Huntington’s, and Parkinson’s disease.

N-methyl-D-aspartate receptors are also expressed across a wide spectrum of non-neuronal cells, including central and peripheral glial cells, endothelium, bone, kidney, pancreas, and others. Astrocytes express functional NMDARs capable of responding to neuronal glutamatergic input and neuroinflammatory processes. Potential roles for endothelial NMDARs is in the area of blood–brain barrier (BBB) function. Uncontrolled glutamate levels in brain are toxic to neurons, damage endothelial function and disrupt BBB integrity. Osteoblast NMDARs stimulated precursor differentiation and contributed to increased bone mineralization, leading to bone matrix deposition. Renal NMDAR activity stimulated vasodilation in the glomerulus, thereby influencing renal blood flow, filtration, and reabsorption in the proximal tubule. In the pancreas, NMDARs are expressed by insulin-producing islet β cells, and influence β cell function and survival. In the lung, airway smooth muscle cells express NMDARs, which may be involved in inflammatory bronchiole hyper-reactivity.

Seven different NMDAR subunits have been identified: the GluN1 subunit, four distinct GluN2 subunits (GluN2A, GluN2B, GluN2C, and GluN2D), and a pair of GluN3 subunits (GluN3A and GluN3B). Functional NMDARs are heterotetramers composed of two glycine or D-serine-binding GluN1 subunits and two glutamate-binding GluN2 (GluN2A-D) subunits or, in some cases, glycine-binding GluN3 (GluN3A/B) subunits. All NMDAR subunits share a common membrane topology that contain four discrete domains: The extracellular amino-terminal domain (ATD) is involved in subunit assembly and allosteric regulation, and contributes to control of ion channel open probability and deactivation speeds. The extracellular ligand-binding domain (LBD) is formed by two discontinuous segments (S1 and S2), and binds agonists and antagonists to control ion channel opening. The transmembrane domain (TMD) contains three transmembrane segments (M1, M3, and M4) and a re-entrant pore loop (M2) which is part of the channel pore, containing a critical asparagine residue that determines calcium permeability of the channel and mediates the magnesium blockade. The intracellular carboxyl-terminal domain (CTD) interacts with multiple cytosolic proteins. GluN2 LBDs contain the glutamate binding site, while GluN1 (or GluN3) LBDs contain the Glycine/D-serine coagonist binding site. In general, activation of NMDARs containing GluN1/GluN2 requires binding of both glycine and glutamate at the extracellular LBDs in addition to release of magnesium block by membrane depolarization at the TMD. Positively charged residues on the surface of the GluN2A LBD assist glutamate binding via a ‘guided-diffusion’ mechanism. On the other hand, Glycine binds to the GluN1 LBD via an ‘unguided-diffusion’ mechanism, whereby glycine finds its binding site primarily by random thermal fluctuations. A recent study show, through cryoelectron microscopy, that the presence of the exon 5 motif, at the ATD of the GluN1 subunit, alters the local architecture of heterotetrameric GluN1/GluN2 NMDA receptors and creates contacts with the LBDs of the GluN1 and GluN2 subunits. The unique interactions established by the exon 5 motif are essential to the stability of the ATD/LBD and LBD/LBD interfaces that are critically involved in controlling proton sensitivity and deactivation. The most widely expressed NMDARs contain the obligatory subunit GluN1 plus either GluN2B or GluN2A or a mixture of the two; therefore, in next sections we will focus on these two subunits.

NMDA Receptors in AD

The defining features of AD include conspicuous changes in both brain histology and behavior. AD brain is characterized microscopically by extracellular amyloid plaques and intraneuronal NFTs. Accumulating evidence indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. The cognitive impairment of AD is closely related to synaptic plasticity, in which NMDAR plays a critical role. Excitatory glutamatergic neurotransmission via NMDAR is critical for synaptic plasticity and survival of neurons. However, excessive NMDAR activity causes excitotoxicity and promotes cell death, underlying a potential mechanism of neurodegeneration occurred in AD. The major factors that affect NMDAR signaling in AD include glutamate availability and the modulation of NMDAR channel functions.

Aβ in AD

In AD, Aβ cascade hypothesis posits an initiating event of amyloidosis, with subsequent tau accumulation preceding downstream brain atrophy and cognitive decline. From amyloid-PET and florbetapir-PET studies, it has been known that Aβ deposition occurs selectively first in the cortex, beginning in temporobasal and frontomedial areas, and successively affecting primary sensory-motor areas and the medial temporal lobe. It was followed by hippocampal regions, then striatum, basal forebrain, thalamus, and finally brainstem nuclei and cerebellum. Deposition of Aβ in the medial parietal cortex appears to be the first stage in the development of AD, although tau aggregates in the medial temporal lobe precede Aβ deposition in cognitively healthy older people.

Aβ is produced by endoproteolysis of the parental amyloid precursor protein (APP), which is achieved by the sequential cleavage of APP by groups of enzymes termed β- and γ-secretases. Aβ is produced as a monomer, but readily aggregates to form multimeric complexes. Human Aβ can exist in diverse assembly states, including monomers, dimers, trimers, tetramers, dodecamers, higher-order oligomers and protofibrils, as well as mature fibrils, which can form microscopically visible amyloid plaques in brain tissues. The original amyloid hypothesis postulated that accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. Cell studies and animal experiments confirmed that oligomeric, soluble Aβ rather than insoluble amyloid plaques exert the toxic effect. Thus, according to the modified amyloid cascade hypothesis, soluble oligomeric assemblies of Aβ induce the neurodegenerative triad.

The Aβ peptide was first identified as a component of extracellular amyloid plaques in the mid-1980s. Now, there have been a large number of studies have provided evidence for the presence of intracellular Aβ within neurons. Immunogold electron microscopy has been carried out to demonstrate that Aβ1-42 can be found in multivesicular bodies (MVBs) of neurons in the human brain, where it is associated with synaptic pathology. Studies also show that Aβ produced intracellularly in the endosome compartments, ER (endoplasmic reticulum), and trans-Golgi network in neurons. The secreted Aβ, which forms the extracellular Aβ pool, could be taken up by cells and internalized into intracellular pools. Aβ binds to the α7 nicotinic acetylcholine receptor (α7nAChR) with high affinity, resulted in receptor internalization and accumulation of Aβ intracellularly. In addition to nicotinic receptors, Aβ internalization has been reported through LRP (low-density lipoprotein receptor related protein), RAGE (scavenger receptor for advanced glycation end products), and NMDAR. Aβ uptake was completely blocked by NMDAR antagonists, evidencing an involvement of this receptor in the re-uptake of the peptide.

Aβ oligomerization initiates within cells rather than in the extracellular space. Much evidence suggests that Aβ oligomers are more potent than Aβ fibrils in eliciting abnormalities in synaptic functions. Moreover, oligomers of Aβ1-42 are considered the most synaptotoxic forms, responsible for early cognitive deficits in AD. Aβ leads to aberrant excitatory network activity and compensatory inhibitory responses involving learning and memory circuits. Intracellular Aβ within the MVBs is mechanistically linked to cytosolic proteasome inhibition, lead to higher Aβ levels and the buildup of tau protein. Low (picomolar range) concentrations of Aβ markedly potentiate synaptic transmission, whereas higher concentrations (low nanomolar range) of Aβ cause synaptic depression by acting on α7nAChR activation.

Accumulation of intracellular Aβ in mitochondria is associated with the multitude of mitochondrial defects described in AD. Aβ is transported into mitochondria via the translocase of the outer membrane machinery and is located in mitochondria cristae. In AD postmortem brain and cellular and animal AD models, mitochondrial dysfunction can be triggered by Aβ. Aβ-induced mitochondrial dysfunction was reported to be related to the interaction of Aβ with different mitochondrial proteins, including proteins of the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix, impairing oxidative phosphorylation and mitochondrial dynamics and increasing reactive oxygen species (ROS) production.

Aβ also induce ER stress. In mature hippocampal cultures, Aβ induce NADPH oxidase (NOX)-mediated superoxide production downstream of GluN2B and impairs ER and cytosolic Ca2+ homeostasis. In rat brain endothelial cells (RBE4 cell line), Aβ increased the levels of several markers of ER stress-induced unfolded protein response (UPR), affected the Ca2+ homeostasis. In turn, ER stress mediated Aβ production or neurotoxicity. Increased the ER stress promoted Aβ production was observed in RGC-5 cells, a cell line identical to the photoreceptor cell line 661W. Knockdown of syntaxin 5 expression enhanced the secretion of Aβ peptides under condition without ER stress in NG108-15 cells. In PC12 cells, the ER stress response factor X-box binding protein 1 (XBP1) prevents Aβ-introduced accumulation of [Ca2+]i.

Aβ was shown to be produced in high amounts in synaptic terminals of the hippocampal dentate gyrus of transgenic mice and deposited in extracellular plaques. Indeed, studies in AD postmortem brain tissue samples and AD animal models support a role for disruption of synaptic Ca2+ regulation in the neurotoxic action of Aβ, which may serve as a trigger for synaptic deterioration driving the cognitive loss in AD. Cognitive function ultimately depends on synaptic plasticity where LTP is associated with synapse growth and LTD is associated with synapse loss. Aβ is associated with the inhibition of LTP and the promotion of LTD. During the induction of LTP, the strong and prolonged release of glutamate from the presynaptic terminal activates AMPA receptors and the subsequent depolarization removes the Mg2+ blockade of the NMDAR channel and allows the influx of Ca2+. This strong activation of NMDARs triggers a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated signaling cascade that eventually leads to an enhanced synaptic strength. On the contrary, a modest activation of NMDARs causes a modest increase in postsynaptic Ca2+ and triggers phosphatases-mediated LTD. Activation of synaptic NMDARs and large increases in [Ca2+]i are required for LTP, whereas internalization of synaptic NMDARs, activation of perisynaptic NMDARs and lower increases in [Ca2+]i are necessary for LTD. LTP induction promotes recruitment of AMPA receptors and growth of dendritic spines, whereas LTD induces spine shrinkage and synaptic loss. Pathologically elevated Aβ may indirectly cause a partial block of NMDARs and shift the activation of NMDAR-dependent signaling cascades toward pathways involved in the induction of LTD and synaptic loss. This model is consistent with the fact that Aβ impairs LTP and enhances LTD. Although the mechanisms underlying Aβ-induced LTD have not yet been fully elucidated, they may involve receptor desensitization or internalization and subsequent collapse of dendritic spines.

Aβ modulated NMDA-induced responses and vice versa; pre-exposure to Aβ decreased NMDA-evoked [Ca2+]i rise and pre-exposure to NMDA decreased Aβ response. In addition, simultaneous exposure to Aβ plus NMDA synergistically increased [Ca2+]i levels, an effect mediated by GluN2B-containing NMDARs. Accumulating evidence demonstrates that glutamate receptors are dysregulated by Aβ oligomers, resulting in disruption of glutamatergic synaptic transmission which parallels early cognitive deficits. In theory, there are several potential roles for the NMDA receptor in Aβ-related mechanisms: first, NMDA receptor function may be an important downstream target of Aβ; second, NMDA receptors may be necessary in the actions of Aβ on synaptic transmission and plasticity; third, NMDA receptor may be a receptor for Aβ, or indirectly; and fourth, NMDA receptor activity may control the formation of Aβ.

The Effect of Aβ on NMDAR Subunits

Expression of NMDAR subunits differentially distribute throughout the brain and change strikingly during development. The glycine/D-serine binding GluN1 subunit is an obligatory subunit in all NMDA receptor subtypes. In accordance with the widespread central nervous system (CNS) distribution of NMDARs, the GluN1 subunit is ubiquitously expressed from embryonic stage E14 to adulthood. The four different glutamate binding GluN2 subunits (GluN2A-D) have pronounced differences in both developmental and regional expression levels and endow NMDA receptors with strikingly different pharmacological and functional properties. In the embryonic brain, only GluN2B and GluN2D subunits are expressed, and the latter is mostly found in caudal regions. During the first two postnatal weeks, GluN2A expression rises steadily to become widely and abundantly expressed in virtually every CNS area in the adult. Meantime, GluN2D expression drops markedly, and in the adult, it is expressed at low levels mostly in the diencephalon and mesencephalon. GluN2B expression is maintained at high levels following birth, peaks around the first postnatal week and becomes progressively restricted to the forebrain. Expression of GluN2C appears late in development, about postnatal day 10, and mainly confined to the cerebellum and the olfactory bulb.

In the adult CNS, particularly in higher brain structures, such as the hippocampus and cortex, GluN2A and GluN2B are the predominant subunits, indicating that they have central roles in synaptic function and plasticity. GluN2C- or GluN2D- containing receptors appear to give rise to ‘low-conductance’ openings with a lower sensitivity to extracellular Mg2+, which may affect the Ca2+ influx generated by synaptic activation of NMDAR. results indicate that GluN1/GluN2D receptors do not contribute to the excitatory postsynaptic current (EPSC) and appear to be restricted to the extrasynaptic membrane. The possibility still exists that the GluN2D subunit is present at the synapse but is preferentially co-assembled with other GluN2 subunits, such as triheteromeric assemblies (GluN1/GluN2B/GluN2D). GluN3A and GluN3B were cloned based on similarity to GluN1 and GluN2 subunits and were the last NMDA receptor subunits to be discovered. GluN3A expression is low embryonically, peaks during early postnatal life, and diminishes to lower levels in adulthood. This expression profile is observed in many regions of the brain. Conversely, GluN3B levels are low around postnatal day 10 and gradually increase into adulthood within the neocortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. GluN3A and GluN3B are expressed by multiple neuronal cell types, including interneurons, pyramidal cells, motor neurons, trigeminal neurons, retinal ganglion and amacrine cells. Although GluN3A is present in oligodendrocytes, it does not seem to be expressed in astrocytes. The GluN3 subunits bind glycine and D-serine, but the functional properties and physiological roles of GluN3-containing NMDA receptors remain elusive. GluN3A acts in a dominant-negative manner to suppress receptor activity. GluN3A containing NMDARs display striking regional and temporal expression specificity, and, unlike most other NMDAR subtypes, they have a low conductance, are only modestly permeable to Ca2+, and pass current at hyperpolarized potentials in the presence of magnesium. While glutamate activates triheteromeric NMDARs composed of GluN1/GluN2/GluN3A subunits, glycine is sufficient to activate diheteromeric GluN1/GluN3A-containing receptors. About GluN3A is expressed in the right place at the right time to regulate spine and synapse development, there are two hypotheses, if the influence of GluN3A is to serve as a ‘synaptic brake’ to limit synapse/spine formation or if it serves as a ‘synaptic marker’ to promote the elimination of spines. found that prolonging GluN3A expression prevents glutamatergic synapse maturation by limiting synapse potentiation and growth, and decreasing spine density, accompanied by major impairments in learning and memory processes. Whereas knocking out endogenous GluN3A conversely accelerates synaptic maturation events.

In line with the large number of subunits and their overlapping expression in several brain regions, many different NMDAR subtypes coexist in the CNS. All NMDAR subtypes are thought to combine two copies of the obligatory GluN1 subunit plus two copies of GluN2 and/or GluN3 subunits. Diheteromeric GluN1/GluN2B and GluN1/GluN2A receptors represent an important fraction of juvenile and adult NMDARs. Triheteromeric GluN1/GluN2A/GluN2B receptors also populate many regions in the adult brain, particularly in the hippocampus and cortex, with estimates of abundance ranging from 15% to >50% of the total receptor population. They may maintain some signaling properties of the GluN2B subunit while having the kinetic properties of GluN1/2A NMDARs. The sensitivity of GluN1/GluN2A/GluN2B triheteromers to the agonists, glutamate and glycine, is intermediate to that of diheteromers. The sensitivity to glycine, conferred by the GluN1 sub-units, is close to that of GluN1/GluN2B receptors, whereas the sensitivity to glutamate, conferred by the GluN2 sub-units, is closer to that of GluN1/GluN2A receptors. Triheteromeric GluN1/GluN2A/GluN2C receptors and GluN1/GluN2B/GluN2D receptors have also been described. Triheteromeric GluN1/GluN2A/GluN2C receptors are the predominant NMDARs in cerebellar granule cells and propose that co-expression of GluN2A and GluN2C in cerebellar granule cells occludes cell surface expression of diheteromeric GluN1/GluN2C receptors. For many agonists, potentiators, and inhibitors as well as endogenous ligands, GluN1/GluN2A/GluN2C NMDARs had intermediate properties compared with diheteromeric receptors. Similarly, triheteromeric GluN1/GluN2A/GluN2D and GluN1/GluN2B/GluN2D complexes populate the rat thalamus and midbrain, as well as the human spinal cord. GluN3A and GluN3B subunits can co-assemble with GluN2 subunits to form triheteromeric GluN1/GluN2/GluN3 receptors that are involved in synapse maturation during brain development.

N-methyl-D-aspartate receptors dysregulation evoked by Aβ and the consequent loss of Ca2+ homeostasis are thought to be related to the early cognitive deficits observed in AD. Many researches have demonstrated that Aβ oligomers and NMDAR contribute to the synaptic dysfunction in AD. The effect of Aβ on synapses is to produce depression of glutamatergic synaptic transmission and reduce surface glutamate receptors and other synaptic components in cultured hippocampal neurons. NMDAR antagonist D-VAP can blocked the Aβ-induced depression of glutamatergic transmission. Aβ accumulation may activate NMDARs at early stages of AD, and that Aβ oligomers can evoke an immediately [Ca2+]i rise through activation of GluN2B-containing NMDARs in cultured cortical neurons. Conversely, Aβ-induced activation of GluN2A-containing NMDARs in non-neuronal cells, namely in Xenopus laevis oocytes and HEK293cells, was previously reported.

The effects of Aβ on the mRNA and protein levels of NMDAR subunits have been extensively studied in vivo and in vitro, although the alterations of the NMDARs remain inconclusive. Some reported that levels of both GluN1 mRNA and GluN1 protein were significantly lower in AD patients. Conversely, other studies evidenced that levels of GluN1 mRNA were unchanged. Moreover, levels of GluN2A and GluN2B mRNA were decreased in AD brain, especially in hippocampus and the entorhinal cortex of postmortem. Whereas levels of GluN2C and GluN2D mRNA did not differ from that in controls. The levels of GluN2A and GluN2B protein were also decreased in AD brain. Other study found that mRNA expression and protein levels for GluN1 and GluN2B were significantly reduced, while GluN2A mRNA expression and protein levels were unchanged in hippocampus.

data show that Aβ oligomers binding to mature hippocampal cells was prevented when the extracellular termini of GluN1 and GluN2B, but not of GluN2A, was blocked, indicating that Aβ oligomers are able to bind NMDARs extracellularly. These were consistent with the results that NMDARs may be direct or indirect targets for Aβ, by the obligatory GluN1 subunit, affecting the activity of these receptors. In the AD brain and human cortical neurons, excitatory synapses containing the GluN2B subunit of the NMDARs appear to be the main sites of Aβ oligomers accumulation. In addition, some studies report that Aβ oligomers may bind to EphB2, a surface tyrosine kinase that binds the NMDARs for maintaining its integrity. EphB2 degradation results in a decrease in surface localization of NMDA receptor subunits like GluN2B, the loss of NMDAR function and reduced LTP.

Some results suggest a circuit in which Aβ facilitates NMDARs activation, which in turn control the formation of Aβ. NMDARs activation, and more particularly extrasynaptic activation, increased production and secretion of Aβ in primary cultures of cortical neurons, which was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing amyloid-β precursor protein (KPI-APP), isoforms exhibiting an important high amyloidogenic potential, followed by a shift from α-secretase to β-secretase-mediated APP processing. An in vivo study indicates that the level of NMNDAR activation may control the effect on Aβ production: low levels of NMDAR activation increase Aβ production while higher levels reduce Aβ production. However, a study using in vivo microdialysis techniques demonstrated that the neuronal activity dependence of Aβ secretion lies in the presynaptic compartment suggesting no NMDAR dependence. The role of NMDAR in production of Aβ is likely complex and requires more investigation.

N-methyl-D-aspartate receptors mediate many forms of synaptic plasticity. These tetrameric receptors consist of two obligatory GluN1 subunits and two regulatory subunits, usually a combination of GluN2A and GluN2B. Among the six regulatory subunits of NMDARs, GluN2A and GluN2B have been the most extensively studied because they are broadly expressed in the brain, predominate in the postnatal cortex, and are believed to play important roles in synaptic plasticity. In the neonatal neocortex GluN2B-containing NMDARs predominate, and sensory experience facilitates a developmental switch in which GluN2A levels increase relative to GluN2B. However, GluN1/GluN2B carry about twofold more charge for a single synaptic event than GluN1/GluN2A channels. More studies showed that GluN2A-dominated synapses are more likely to induce LTD than GluN2B-dominated synapses, while GluN2B-dominated synapses have a greater capacity to be potentiated. GluN2A co-immunoprecipitates with neuronal nitric oxide (NO) synthase more effectively than GluN2B. Although this interaction is likely indirect, the association raises the interesting possibility that NO-mediated presynaptic forms of LTP and LTD may be preferentially linked to GluN2A-mediated signaling pathways. Activated CaMKII binds strongly to GluN2B, which is required for LTP induction. However, both GluN2A-containing and GluN2B-containing NMDARs are capable of supporting bidirectional synaptic plasticity. GluN2A and GluN2B are present as either diheteromers (GluN1/GluN2A or GluN1/GluN2B) or triheteromers (GluN1/GluN2A/GluN2B). In isolated GluN2A-only or GluN2B-only synapses, GluN1/GluN2A diheteromeric channels exhibit faster rising and decaying currents than GluN1/GluN2B diheteromeric channels. GluN1/GluN2A/GluN2B triheteromeric channels appear to exhibit intermediate decay time courses between the two diheteromeric channel types.

Proteins interacting with NMDAR subunits are therefore important determinates for the direction of synaptic plasticity. The differential interaction of GluN2A and GluN2B subunits to membrane-associated guanylate kinase (MAGUKs) is controversial. It was once believed that GluN2A preferentially bound to postsynaptic density protein-95 (PSD-95), while GluN2B preferentially bound synapse-associated protein 102 (SAP102). GluN2B interacts directly with Ras-guanine nucleotide releasing factor 1 (Ras-GRF1), and synaptic Ras GTPase activating protein (RasGAP), presumably through SAP102. The unique associations are likely to affect the induction of plasticity. Moreover, these interactions were thought to control distinct synaptic localization of GluN2A and GluN2B. However, a recent biochemical study using a serial immunoprecipitation suggests that MAGUK proteins such as PSD-95 and SAP102 interact with diheteromeric GluN1/GluN2A and GluN1/GluN2B receptors at comparable levels. Additional studies are needed to clarify the association of NMDAR subunits with MAGUK family members and what effects these associations may have on receptor localization and on plasticity signaling pathways.

Our results suggested that enhancement of GluN2A activity and/or the reduction of GluN2B activity may be used in order to halt the early Aβ-mediated synaptic dysfunction. GluN2A and GluN2B subunits have opposite roles in regulating [Ca2+]i homeostasis. In rat cerebral cortical neurons, Aβ, like NMDA, increase [Ca2+]i levels mainly through activation of GluN2B. Conversely, GluN2A antagonism potentiates [Ca2+]i rise induced by a high concentration of Aβ (1 μM). Simultaneous exposure to Aβ and NMDA affects the response to GluN2B-composed NMDARs, largely causing mitochondrial depolarization and mitochondrial Ca2+ (mitCa2+) retention. Aβ-induced ER stress and hippocampal dysfunction were prevented by ifenprodil, an antagonist of GluN2B subunits, while the GluN2A antagonist NVP-AAM077 only slightly attenuated Aβ-induced neurotoxicity. Moreover, exposure to Aβ caused a decrease in total and polymerized levels of beta-III tubulin and polymerized alpha-tubulin in mature hippocampal cells, which could be prevented by MK-801, memantine, and ifenprodil, suggesting a role for GluN2B-containing NMDARs in Aβ toxicity.

GluN2A and GluN2B are the major subunits of functional NMDARs. Some studies have suggested that GluN2A and GluN2B may differentially mediate NMDAR function at synaptic and extrasynaptic locations and play opposing roles in excitotoxicity. In the postsynaptic membrane of excitatory neurons, the density of NMDARs is higher in dendritic spines, within the postsynaptic density (PSD), considered synaptic NMDARs, than in the dendritic shaft and somatic membrane. At the PSD, the receptors form a large macromolecular NMDAR complex (NRC), containing a vast collection of scaffolding, adaptor and effector proteins that are involved in activation of downstream signaling cascades and regulation of NMDAR function, membrane stability and trafficking. Extrasynaptic NMDARs are localized at sites further from the PSD, on the spine neck, the dendritic shaft or soma. Perisynaptic NMDARs are located on the plasma membrane (PM) within 200–300 nm of the PSD. The perisynaptic region may contain mobile receptors that are in transit to and from the PSD. Synaptic and extrasynaptic NMDARs are gated by different endogenous co-agonists: D-serine for synaptic NMDARs and glycine for extrasynaptic NMDARs. Both co-agonists are of glial origin. It was proposed that GluN2A- and GluN2B-containing receptors are predominantly found synaptically and extrasynaptically, respectively. For NMDAR redistribution plays a larger role during development, when there is a synaptic switch from GluN2B to GluN2A-containing receptors. In addition, it has been found that synaptic and extrasynaptic NMDA receptors have opposing effects in determining the fate of neurons. Calcium entry through synaptic GluN2A-containing NMDARs induces activity of cAMP response element binding protein (CREB) and gene expression of CREB-evoked brain-derived neurotrophic factor (BDNF), which is involved in the neuroprotective action of synaptic glutamatergic transmission. In contrast, Ca2+ entry through GluN2B-containing NMDARs, which are expressed extrasynaptically, triggers the CREB shut-off pathway. There is some evidence that synaptic NMDARs support LTP, while extrasynaptic NMDARs mediate LTD in the mature brain. Specific NMDAR subunits are not confined to particular subcellular locations on PM. Some evidences shown that GluN2A- and GluN2B-subtypes are present at both synaptic and extrasynaptic sites. These suggest that any difference in signaling by synaptic and extrasynaptic NMDARs must be due to intracellular signaling pathways rather than subunit identity or mobility. And some researchers thought that these results were partially refuted on the basis that these experiments were carried out on developing hippocampal cultured neurons; the same results may not be found under in vivo conditions.

Certain interactions of NMDAR subunits with distinct signaling molecules may occur at synaptic but not at extrasynaptic sites. Extrasynaptic NMDARs are exposed to ambient glutamate, whether this glutamate concentration is high enough to tonically activate extrasynaptic NMDARs remains controversial. Although microdialysis studies report that ambient glutamate concentrations in vivo are high enough to activate extrasynaptic NMDARs, a study suggests that glutamate transporters regulate ambient glutamate concentrations at a level that is too low to cause significant receptor activation. While, some reports that glutamate that is released into the extracellular space mainly from glial processes may result in the persistent activation of extrasynaptic GluN2B receptors, which are of high affinity and are sensitive to low concentrations of glutamate.

Activation of synaptic NMDARs and large increases in [Ca2+]i are required for LTP, whereas internalization of synaptic NMDARs, activation of extrasynaptic NMDARs and lower increases in [Ca2+]i are necessary for LTD. LTP induction promotes recruitment of AMPARs and growth of dendritic spines, whereas LTD induces spine shrinkage and synaptic loss. Importantly, glutamate spillover from synapses or glutamate released from astrocytes activates extrasynaptic NMDARs. Extrasynaptic NMDARs are activated not only at pathological situations, but also by bursts of activity that can occur under physiological situations. Retinal ganglion cells express only extrasynaptic NMDARs and are invulnerable to NMDA neurotoxicity. Synaptic NMDARs can also cause neurotoxicity and can induce LTD. Furthermore, demonstrate that activation of synaptic or extrasynaptic NMDAR alone stimulated pro-survival but not pro-death signaling, for they had overlapping but not opposing effects on genomic responses. Low-dose NMDA preferentially activated synaptic NMDAR and stimulated the extracellular signal-regulated kinase 1/2 (ERK1/2)-CREB-BDNF pro-survival signaling, while higher doses progressively activated increasing amount of extrasynaptic NMDAR along with synaptic NMDAR and triggered cell death program. While, suggested that the subunit composition of NMDARs rather than their cellular location determines the final effect of the activation of the NMDARs by glutamate.

N-methyl-D-aspartate receptors are highly mobile at both synaptic and extrasynaptic membranes. Importantly, the surface mobility of NMDARs appears to change with development in a subunit composition-specific manner. GluN2A-containing NMDARs are less mobile than GluN2B-containing NMDARs, and the synaptic residency time of GluN2B-containing NMDARs decreases over development. This decrease in synaptic dwell time of GluN2B containing NMDARs is mediated by Reelin, an extracellular matrix protein. Regulatory mechanisms underlying synaptic and extrasynaptic NMDAR distribution include: protein–protein interactions, phosphorylation, palmitoylation, ubiquitination, role of proteases, such as calpain.

Aβ-induced synaptic depression may result from an initial increase in synaptic activation of NMDARs by glutamate, followed by synaptic NMDAR desensitization, NMDAR internalization, and activation of extrasynaptic or perisynaptic GluN2B-enriched NMDARs, which have a key role in LTD induction. On one hand, Aβ downregulates the synaptic NMDAR response by promoting NMDAR endocytosis, leading to either neurotoxicity or neuroprotection. On the other hand, Aβ enhances the activation of extrasynaptic NMDARs by decreasing neuronal glutamate uptake and inducing glutamate spillover, subsequently causing neurotoxicity. Aβ oligomers bind with high affinity to cell surface cellular prion protein (PrPC). PrPC and Fyn are enriched in PSD. Metabotropic glutamate receptor, mGluR5, has ability to couple Aβ-PrPC with Fyn, controls the transmission of neurotoxic signals to intracellular substrates. Aβ engagement of PrPC activates Fyn to phosphorylate the GluN2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Pretreatment with the 6D11 antibody to PrPC could prevented the Aβ-induced synaptic dysfunction. Aβ also binds to the α7nAChR, resulting in increased Ca2+ influx, calcineurin activation and dephosphorylation and activation of STEP61. Increased STEP61 activity leads to Fyn inactivation and reduced NMDAR exocytosis, as well as enhanced GluN2B Y1472 dephosphorylation and increased NMDAR internalization.

Tau and NMDA Receptors

Tau is a major component of the NFT that represent a pathological hallmark of AD. In the healthy brain, tau is an exclusively axonal protein, engaged in the assembly and stability of microtubules. In contrast, in the AD brain, tau is hyperphosphorylated and forms fibrils that appear as neuropil threads in dendrites and as NFTs in the somatodendritic compartment and axons. It had provided strong evidence cerebral amyloid deposition precedes cerebral tau pathology in familial autosomal dominant AD, While, the appearance of NFTs precedes Aβ pathology in the vast majority of affected regions in sporadic AD. first ruled out the possibility that tau reduction altered Aβ levels or aggregation, and uncoupled Aβ from downstream pathogenic mechanisms.

Tau not only contributes to axonal structure by maintaining microtubule stability, but also is important in the regulation of synaptic function. Tau is required for Fyn-mediated NMDAR activation in the PSD, and tau has been shown to be essential for the induction of LTD as well as BDNF-dependent morphological plasticity. Fyn, a member of the Src family of tyrosine kinases, can phosphorylate tau at its tyrosine 18 residue to generate pY18-tau and can bind to tau through one or more proline-rich (PxxP) motifs in tau. Fyn phosphorylates the NMDAR subunit GluN2B at Y1472, which strengthens the interaction between NMDARs and PSD-95 in the PSD and enhances the activity of GluN2B-containing NMDARs. Some experiments indicated that tau is normally highly enriched in axons relative to dendrites, but in response to Aβ is extensively redistributed into the somato-dendritic compartment. Excess Fyn accompanies the excess tau in AD dendrites and upregulates NMDA receptor activity there, flooding the dendrites with harmful levels of calcium. This calcium-driven excitotoxicity can damage postsynaptic sites and cause neuron death. Some results confirmed that glutamate-induced excitotoxicity is inhibited by reduction of tau and exacerbated by overexpression of tau. In turn, glutamate-induced excitotoxicity increased tau expression and phosphorylation. Recently, it has been reported that activation of extrasynaptic NMDA receptors induces tau overexpression, with a simultaneous neuronal degeneration and decreased neuronal survival.

Presynaptic NMDAR

Traditionally, NMDARs are thought to be located at the postsynaptic membrane, while recent anatomical and physiological evidence demonstrates that they may also exist at presynaptic terminals. Presynaptic NMDARs (preNMDARs) can regulate presynaptic glutamate release, and reshape synaptic transmission and plasticity. Therefore, preNMDAR subunit composition is critical for modulating where and how preNMDARs influence glutamate release. The subunit composition of preNMDARs shows strong variability, depending on the brain region, all four GluN2 subunits (Glu2A-D) as well as GluN3A can be incorporated. The presynaptic GluN2B subunit has been found in many brain regions, such as the hippocampus, the cerebellum, the entorhinal cortex, somatosensory and visual cortex. Although appears and peaks later during development, GluN2A subunit can also be incorporated into preNMDAR sites. At cerebellar parallel fiber-Purkinje cell synapses, preNMDARs are predominately GluN1/GluN2A diheteromeric. Furthermore, GluN2B and GluN3A subunits, likely combining into triheteromeric GluN1/GluN2B/GluN3A, are essential preNMDARs in the developing L2/3 visual cortex.

It has been reported that preNMDARs may regulate both spontaneous and evoked release. Although the two forms of release were initially thought to employ the same machinery, the emerging evidence indicates that preNMDARs control evoked and spontaneous release by distinct mechanisms. PreNMDARs may control spontaneous release independently of Mg2+ and Ca2+ while regulating evoked release in a frequency-dependent manner by relying on the more conventional Mg2+-dependent pathway. showed that preNMDARs in L5 pyramidal cells regulate evoked and spontaneous release via RIM1αβ and JNK2-dependent pathway, respectively.

In addition, the activation of preNMDARs is necessary for the induction of LTD, but it is noteworthy that preNMDARs roles shift over development. Induction of LTD in visual cortex pyramidal cells of young mice (before postnatal 20 days) requires activation of presynaptic, whereas in older mice, the induction of LTD requires postsynaptic NMDARs activation. Contrast to this results, show that in the somatosensory cortex of 2- to 3-week-old rats and mice, it is postsynaptic, not preNMDARs that required for LTD induction. This contradictory result may be due to different brain regions observed. Not only being required for the induction of LTD, preNMDARs also involve in LTP induction. reported that preNMDARs play a pivotal role in the induction of LTP at mouse corticostriatal synapses. Activation of preNMDARs induces BDNF secretion via enhancing Ca2+ signals in the axonal terminals, indicating that preNMDARs are equally essential as postsynaptic NMDARs in LTP induction.

found that subjects with mild cognitive impairment (MCI) displayed a paradoxical elevation in glutamatergic presynaptic bouton density, which then depletes and drops with disease progression. These results pointed out that dystrophic neurite generation and reduced presynaptic bouton densities detrimentally influence neurotransmission and cognitive function in later stages of AD. Although some advances have been made, much work still need to clarify the precise functions and molecular mechanisms on preNMDAR.

Glial NMDAR

While neuronal NMDARs have been widely studied, NMDARs are also expressed in many non-neuronal cells, including astrocytes. Compared to neuronal receptors, astrocytic NMDA receptors are poorly understood. The emerging evidence suggests that astrocytic NMDARs have distinct structural and functional properties, including weak susceptibility to Mg2+ blockade and less Ca2+ permeability. NMDAR expression and function in astrocytes has been demonstrated in cultured astrocytes and mouse neocortex. In human primary astrocytes, all seven identified NMDAR subunits (GluN1, GluN2A-D, GluN3A-B) were found. Increasing data demonstrate that astrocytes express NMDARs with a triheteromeric configuration combining GluN1, GluN2C or D, and a GluN3 subunit. Glutamate and QUIN both could activate astrocytic NMDARs, which in turn enhances Ca2+ influx and induces signaling cascade. It is established that astrocytic functional NMDARs are able to respond to neuronal glutamatergic input, which accompany with dynamic intracellular Ca2+ rise triggering gliotransmitter-mediated regulation of synapses function. Astrocytic NMDARs may also be involved in neuroinflammatory processes, and contribute to morphological transformations characteristic of reactive astrogliosis and mediate the release of proinflammatory cytokines. Notably, astrocytic NMDARs maybe contribute to AD due to their roles in facilitating glutamate excitotoxicity. Our research found that Aβ-induced early synaptotoxicity can be exacerbated after treatment with antagonism of astrocytic GluN2A and GluN2B, and nerve growth factor (β-NGF) is may be as a mediator in the synaptoprotection of astrocytic GluN2 activation. In co-cultures system, pre-treatment of astrocytes with 1 μM or 10 μM NMDA to activate GluN2A or GluN2B, before exposure to Aβ1-40, was found to prevent the Aβ introduced PSD-95 and synaptophysin decreased. While blockade of astrocytic GluN2A with TCN-201 or GluN2B with ifenprodil respectively both aggravated the synaptotoxic effects of Aβ.

Additionally, NMDARs are also expressed by oligodendrocyte lineage cells, as mediators of intracellular Ca2+ accumulation, leading to reduced oligodendrocyte survival and white matter damage. The dominant force behind NMDA-induced currents in mature oligodendrocytes is actually elevated extracellular K+ released upon activation of neuronal or astrocytic NMDARs. Increased in oligodendrocytic Ca2+ would be gated by transient receptor potential cation channel (TRP) A1. Oligodendrocyte precursor cell (OPC) NMDARs may also contribute to myelination. Activation of NMDARs in OPC cultures increased migration, myelin basic protein expression and differentiation.

Rather surprisingly, a recent study observed that NMDARs were present in primary cultures of microglia from mice cortex and hippocampus, and exposure to NMDAR co-agonists resulted in evoked inward currents and intracellular Ca2+ increases sensitive to inhibition by the non-competitive NMDAR channel blocker, MK801. NMDAR activation in microglia leads to significant ERK1/2 phosphorylation. ERKs phosphorylation, namely, NMDAR interact with and signaling to mitogen-activated protein kinase (MAPK) depends on CaM and NCS1 in neurons, whereas the signaling via NMDAR in microglia only depends on CaM. NMDAR function was potentiated in microglia from the APPSw,Ind transgenic mice, indicating that the NCS1–NMDAR interaction is relevant for receptor function in the microglia of the AD mouse model.

Metabotropic NMDAR

It was thought that NMDAR-dependent synaptic plasticity was controlled entirely by Ca2+ influx, and the increased cytoplasmic Ca2+ acts as a second messenger in the postsynaptic neuron. More recently provocative emerging evidence assumes that, upon binding of glutamate, NMDARs can produce long-term changes in synaptic function in the absence of calcium conductance. In other words, NMDAR can act as a metabotropic receptor and signal metabotropically, without the need for Ca2+ influx through the channel.

A conventional view proposes that NMDARs triggers LTP via a high level of Ca2+ influx, while metabotropic receptor arises from synaptic depression induced by low frequency stimulation (LFS), which is called as NMDAR-dependent LTD. Recent results demonstrated that glutamate binding alone is sufficient to induce conformational changes of NMDARs, triggering p38MAPK signaling cascades, and in turn to induce LTD. It is noteworthy that Ca2+ rise could induce LTP; while keeping at the baseline level of intracellular Ca2+ is necessary for metabotropic NMDAR activation, which leads to synaptic depression.

Consistent with this metabotropic signaling, some researchers found preNMDARs may control spontaneous release without need of Mg2+ and Ca2+, while evoked release was sensitive to Mg2+. PreNMDARs promote transmitter release partly via protein kinase C signaling. These data suggest that preNMDARs may signal metabotropically, and further support the emerging propose that evoked and spontaneous release are through distinct machinery. Although mounting findings support an ion flux-independent mechanism for NMDAR-dependent LTD, it has been challenged by some recent discoveries. It is more possible that two distinct forms of NMDAR-dependent LTD co-exist indeed: one requires ion-flux and the other does not.

In addition, some studies demonstrated that astrocytic NMDARs may also act through metabotropic signaling pathways, in which a phospholipase C-mediated endoplasmic reticulum Ca2+ rise and activation of protein kinase Cδ may be involved, but much work remains to clarify the complex mechanism.

Early synaptic dysfunction in AD is associated with increased levels of Aβ oligomers, which causes a rapid NMDAR-dependent synaptic depression and spine loss. While, some studies showed that Aβ-induced NMDAR-dependent synaptic depression did not require ion flux through the receptor, and was blocked by AP-5, but not MK-801, suggesting a metabotropic effect of NMDARs contributes to Aβ-induced synaptic dysfunction. It may be a common mechanism between metabotropic NMDAR-dependent LTD and Aβ-induced synaptic depression.

Treatment

The current therapeutic arsenal of AD comprise of two classes of medications: the cholinesterase inhibitors (ChEIs), which include galantamine and rivastigmine (both approved for use in mild to moderate AD) and donepezil (approved for use in mild to severe AD); and the non-competitive NMDA receptor antagonist memantine (approved for use in moderate to severe AD). Combining ChEIs and memantine could offer greater benefits on behavior, cognition, and global outcomes. However, these drugs provide only symptomatic benefits in AD. Any CNS disorder in which neuronal loss is related to glutamate-induced excitotoxicity has the potential to be treated by the inhibition of NMDARs. Phencyclidine, ketamine, MK-801 (dizocilpine) and memantine all target NMDARs. But due to severe side effects of phencyclidine, ketamine, and MK801, such as high affinity for and long dwell time on the receptor, their clinical application is hindered. By contrast, memantine has lower affinity and is well tolerated, thus is used to treat moderate to severe AD. Inspiringly, riluzole, a new inhibitor of glutamate release and postsynaptic glutamate receptor signaling, is now in a phase II trial in mild AD patients.

Memantine has an inhibitory effect on NMDAR-mediated excitotoxicity, strong voltage dependency, and rapid unblocking kinetic properties. Similar to Mg2+, it blocks the NMDAR and does not leave it in the presence of tonic pathological over-activation of the receptor, while allowing the transmission of transient physiological signals crucial for memory and learning processes. It has been shown that memantine increases the release of neurotrophic factors from astroglia, which may account for its survival effect, and exerts a neuroprotective effect. To date, memantine is the only NMDAR antagonist that is clinically approved and preferentially acts as an antagonist of non-synaptic NMDARs. Extrasynaptically located NMDARs have a relevant role in neurodegeneration. Activation of extrasynaptic receptors may not only regulate expression of tau, but also induce transcriptional inactivation of CREB and also contribute to early synaptic dysfunction. The low-affinity antagonist memantine will be the focus of growing interest in targeting extrasynaptic GluN2B-containing NMDARs. In addition, selective enhancement of synaptic activity by low doses of NMDA, or reduction of extrasynaptic activity by memantine, halts Aβ-induced neurotoxicity. The concomitant blockade of GluN2A-containing receptors impaired the activation of protective pathways. In contrast, the selective inhibition of GluN2B-containing NMDARs may be beneficial because it prevents neuronal cell death but leaves the protective pathways intact. Therefore, it is almost certain that in the future, neuroprotective drugs for AD should aim at both the enhancement of synaptic activity and the disruption of extrasynaptic GluN2B-containing NMDAR-dependent death signaling, the non-selective NMDA antagonists cannot be effective as neuroprotective agents.

The first GluN2B-selective drug is ifenprodil, which inhibits GluN2B receptor-mediated currents with an IC50 of 0.34 μM, whereas its affinity for GluN2A receptors is 400-fold lower, with an IC50 of 146 μM. Ifenprodil binds to the N-terminal lysine/isoleucine/valine-binding protein (LIVBP)-like domain of GluN2B and acts as a non-competitive antagonist in a use-dependent and voltage-independent manner. There have been several second generation ifenprodil analogs, including CP-101,606 (traxoprodil) and Ro 25-6981 (Table 1), that exhibit a much greater selectivity for GluN2B subunits. Indole-2-carboxamide derivatives, such as RG-13579 and RG-1103, are a new group of GluN2B-selective antagonists. RG-13579 and RG-1103 bind GluN2B-containing receptors 1,600- and 13,600-fold more selectively, respectively, than they bind GluN2A-containing receptors. Inhibition of the interactions of GluN2B with Fyn and GluN2B tyrosine phosphorylation may contribute to the CP-101,606-induced downregulation of NMDAR function. In vivo [3H]MK-801 binding study shows that NMDAR activity in the rodent forebrain can be inhibited completely by channel blockers, AZD6765 (lanicemine) and MK-801, but only partially (∼60%) by GluN2B receptor antagonists, CP-101,606, MK-0657 (CERC-301), EVT-101, Ro 25-6981 and radiprodil, at doses that completely occupied GluN2B receptors. demonstrated that a single dose of either the non-selective NMDA receptor blocker ketamine or the selective GluN2B antagonist CP-101,606 can enhance ex vivo hippocampal LTP in rats 24 h after treatment.

Zinc binds to the leucine/isoleucine/valine binding protein (LIVBP)-like domain of GluN2A, displays a greater than 50-fold selectivity for GluN1/GluN2A over GluN1/GluN2B receptors. GluN2A-selective negative allosteric modulator (NAM) bound LBD heterodimer, corresponding to active and inhibited receptor states reveal a molecular switch in the modulatory binding site that mediate the allosteric inhibition. Zinc and ifenprodil bind with high affinity to the ATDs of GluN2A and GluN2B, respectively. In hippocampal synapses, zinc decreased the EPSC peak and prolonged the deactivation. Ifenprodil, in contrast, decreased the peak but did not prolong the deactivation.

Binding sites of GluN2A-NTD (N-terminal domain) and GluN2B-NTD retain selective high affinity for their ligand, zinc and ifenprodil. However, each ligand produces only partial inhibition, and maximal inhibition requires occupancy of both GluN2-NTDs by their respective ligands. With regard to the triheteromeric NMDARs, such as GluN1/GluN2A/GluN2B, a single GluN2A or GluN2B subunit is sufficient to confer high affinity to zinc or ifenprodil, but the maximal level of inhibition is greatly reduced compared with diheteromeric NMDARs. Similarly, GluN1/Glu2A/GluN2C receptors are inhibited by zinc with high potency but low efficacy. Therefore, interactions between homologous NTDs determine the unique pharmacological properties of triheteromeric NMDARs. The sensitivity of triheteromeric NMDARs to zinc or ifenprodil provides an example of intermediate pharmacology, with reduced potency and efficacy.

A recent work identifies a new series of NAMs to study GluN2C and GluN2D function in brain circuits. The prototypical compound, NAB-14, is >800-fold selective for recombinant GluN2C/GluN2D over GluN2A/GluN2B in Xenopus oocytes and has an IC50 value of 580 nM at recombinant GluN2D-containing receptors expressed in mammalian cells, which inhibition reside in the GluN2D M1 transmembrane helix. NAB-14 inhibits GluN2D-mediated synaptic currents in rat subthalamic neurons and mouse hippocampal interneurons, but has no effect on synaptic transmission in hippocampal pyramidal neurons, which do not express GluN2C or GluN2D. data provide evidence that hippocampal interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing. These works suggest that selectively modulating brain circuits involving the GluN2C and GluN2D subunits is likely to be developed into clinical therapies.

GluN3A subunit was cloned almost two decades ago, followed by cloning of the GluN3B subunit in the beginning of this century. The GluN3 subunits appears to function as modulatory subunits that reduce the susceptibility of NMDA receptors to Mg2+-blockage and reduce Ca2+-permeability. Furthermore, GluN3 subunits are involved in synapse maturation, synaptic plasticity, and neuroprotective. Overexpression of GluN3A might attenuate NMDAR mediated cell death by reducing Ca2+ permeability of existing NMDARs. Consistent with the idea that GluN3A might offer neuroprotective benefits, high levels of GluN3A expression during early brain development might explain why excitotoxicity is not more prevalent at ages before the maturation of inhibitory circuitry. GluN3A dysfunction may contribute to neurological disorders involving NMDARs, and the subunit offers an attractive therapeutic target given its distinct pharmacological and structural properties. The study of GluN3A pharmacology is still in its infancy. However, it is clear that GluN3A shares more commonalities with GluN1 than it does with GluN2 subunits. The GluN3A NTD constitutes a crucial regulatory determinant of GluN1/GluN3A receptor function. A hemophilic intersubunit interaction amongst the GluN3A NTDs and the transition region between GluN3A NTD and LBD constitute major structural determinants underlying the low efficacy of glycine-gated GluN1/GluN3A receptors. Glycine binds GluN3A with much higher affinity than it binds GluN1, rodent GluN3A, Kd = 40 nM, 650 times less than that for GluN1, and human GluN3A, Kd = 535 nM. D-serine also binds human and rat GluN3A with high affinity. Very little is known about how GluN3A-containing receptors can be pharmacologically blocked. have succeeded in identifying one novel competitive antagonist, identified 6-hydroxy-[1,2,5] oxadiazolo [3,4-b] pyrazin-5(4H)-one (TK80), with preference for the GluN3B subunit. In addition, they serendipitously identified two novel antagonists, [2-hydroxy-5-((4-(pyridin-3-yl) thiazol-2-yl) amino] benzoic acid (TK13) and 4-(2,4-dichlorobenzoyl)-1H-pyrrole-2-carboxylic acid (TK30), that appear to be non-competitive GluN3 antagonists. When GluN1/GluN3A diheteromers are expressed in heterologous systems, they exhibit little electrophysiological block by the classic NMDAR antagonists APV, MK-801, or memantine. Interestingly, GluN1/GluN2/GluN3A triheteromeric receptors may also be blocked by antagonists targeting GluN2 subunits, as receptors composed of GluN1/GluN2B/GluN3A triheteromers and GluN1/GluN2B diheteromers are similarly blocked by high concentrations of the GluN2B antagonist ifenprodil. One might predict that, compared to GluN1/GluN2B diheteromers, GluN1/GluN2B/GluN3A triheteromers might be less sensitive to lower concentrations of ifenprodil where GluN2B specificity is greater, as previous studies have shown that the magnitude of ifenprodil block depends on the number of GluN2B subunits contained within the NMDAR complex.

Death-associated protein kinase 1 (DAPK1), Ca/calmodulin (CaM)-dependent protein kinase II α (CaMKIIα), and protein kinase A (PKA) are able to phosphorylate NMDARs. A novel approach for preventing neurotoxicity is to inhibit the phosphorylation of GluN2B-containing NMDARs by CaMKIIα. The CaMKIIα antagonist KN-93, a methoxybenzene sulfonyl derivative that competitively inhibits calmodulin binding to CaM kinase with a Ki of 0.37 μM, reduces the effect of CaMKIIα-mediated GluN2B phosphorylation. Protein phosphatase 1 (PP1), highly abundant protein in nerve cells, which co-localizes with the GluN2B subunits of NMDARs, is able to dephosphorylate the Ser1303 residue of GluN2B-containing NMDARs and prevent CaMKII from phosphorylating the receptors, thereby preventing Ca2+ overload inhibiting neurodegeneration. Additionally, in the culture cortical neurons, treatment with 17-β-estradiol (E2) and estradiol receptor, the G-protein-coupled receptor 30 (GPR30) agonist G1 (Ki of 11 nM) attenuated the excitotoxicity induced by NMDA exposure. The short-term activation of GPR30 does not affect the expression of either GluN2A- or GluN2B-containing NMDARs; however, it depresses GluN2B subunit phosphorylation at Ser-1303 by inhibiting the dephosphorylation of DAPK1. The neuroprotection mediated by GPR30 is dependent on G-protein-coupled signals and ERK1/2 activation. Studies have shown that tricyclic desipramine and the serotonin-selective reuptake inhibitor (SSRI) fluoxetine also inhibit NMDA-induced currents in cortical cell cultures. Fluoxetine is a selective inhibitor of GluN2B-containing NMDARs (concentration that causes 50% inhibition, IC50 = 9.74 μM), whereas desipramine inhibits both GluN1/GluN2A (IC50 = 5.10 μM) and GluN1/GluN2B (IC50 = 3.61 μM) subtypes. observed that inhibition by desipramine (IC50 = 3.13 μM) was voltage-dependent, and the drug was unable to bind to NMDARs that were blocked by Mg2+, whereas the inhibition by fluoxetine (IC50 = 10.51 μM) was voltage-independent, and an association with the NMDAR was still possible in the presence of a Mg2+ block.

A recent work suggest that the drugs targeting NMDA receptor function or downstream signaling cascades, can restore network and may be effective in treating AD. At the synapse, the NMDA receptor subunits combined with the post-synaptic related proteins (such as PSD-95) to form a macromolecular complex, which is central for mediating receptor-activated signaling cascades; thus a strategy uncoupling the NMDA receptor from PSD-95 would eliminate excitotoxicity. It is known that Fyn phosphorylating the GluN2 facilitate interaction of the NMDAR complex with PSD-95, linking NMDARs to excitotoxic downstream pathway. It has been demonstrated that disruption of this interaction prevents excitotoxicity without affecting synaptic NMDA currents. Some studies have suggested that agonist binding to NMDARs can signal cascade independently of Ca2+ influx through the receptor. These findings may lead to new pharmacological approaches to target specific synaptic signaling pathway in AD. Therefore, there is an urgent need to develop novel pharmacological compounds selectively targeting specific receptor subunits and the various signaling pathways.

Conclusion and Perspectives

As Alzheimer’s progresses, brain cells die and synapses are lost, causing cognitive symptoms to worsen. All of the prescription medications currently approved to treat Alzheimer’s symptoms in early to moderate stages are from a class of drugs called ChEIs. The non-competitive NMDA receptor antagonist memantine and a combination of memantine and donepezil are approved by the United States Food and Drug Administration (FDA) for treatment of moderate to severe AD. While current medications cannot stop the damage Alzheimer’s causes to brain cells, they may help lessen or stabilize symptoms for a limited time. The researches focusing mainly on Aβ amyloid deposits and tau protein aggregates forming NFTs have yielded disappointing results. As such, there is a need to develop effective and safe disease modifying treatments that directly target AD pathology and alter the course of AD progression. It has been motivating researchers to study drugs in earlier stages of the disease, particularly in pre-clinical AD, even before MCI, instead of mild-to-moderate AD trials.

AD, related to glutamate-induced excitotoxicity, has been treated by the inhibition of NMDARs. However, clinical trials that have applied high affinity NMDA antagonists have so far failed. This failure has been due to a lack of efficacy and unexpected paradoxical side effects. These negative results can be explained by the opposing role of the different subtypes of NMDARs, and all subtypes are inhibited by the administered drugs. The heteromeric nature of NMDARs provides a wide variety of receptor subtypes, allowing for a rich diversity in receptor signaling properties. While synaptic GluN2A-containing NMDARs activation is involved in neuroprotection, the stimulation of extrasynaptic GluN2B-containing NMDARs triggers cell destruction pathways. The findings that GluN2A- and GluN2B-containing NMDARs can be selectively inhibited by antagonists may be useful in determining pharmacological targets for drug development. In addition, the sensitivity of triheteromeric NMDARs to zinc or ifenprodil with reduced potency and efficacy. It will require the generation of NMDAR antagonists that are highly efficient and highly selective. Modern research is trying to discover effective disease-modifying therapies, which specifically target the pathophysiologic signaling, to delay onset and progression of the disease. In future, continuous and sustained efforts are still needed before NMDAR-targeted interventions can transform into effective treatments.

Author Contributions

JL and LC wrote most part of the review. YS and HL searched the references and participated in the writing. YW designed the review and revised it.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 334

  1. 1.

    Aarts M. Liu Y. Liu L. Besshoh S. Arundine M. Gurd J. W. (2002 ). Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 298 846–850.

    Not in our library10.1126/science.1072873

  2. 2.

    Abrahamsson T. Chou C. Y. C. Li S. Y. Mancino A. Costa R. P. Brock J. A. (2017 ). Differential regulation of evoked and spontaneous release by presynaptic NMDA receptors. Neuron 96 839.e5–855.e855.

    Not in our library10.1016/j.neuron.2017.09.030

  3. 3.

    Al-Hallaq R. A. Conrads T. P. Veenstra T. D. Wenthold R. J. (2007 ). NMDA di-heteromeric receptor populations and associated proteins in rat hippocampus. J. Neurosci. 27 8334–8343.

    Not in our library10.1523/jneurosci.2155-07.2007

  4. 4.

    Almeida C. G. (2006 ). Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J. Neurosci. 26 4277–4288.

    Not in our library10.1523/jneurosci.5078-05.2006

  5. 5.

    Anaparti V. Ilarraza R. Orihara K. Stelmack G. L. Ojo O. O. Mahood T. H. (2015 ). NMDA receptors mediate contractile responses in human airway smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 308 L1253–L1264.

    Not in our library10.1152/ajplung.00402.2014

  6. 6.

    Anderson M. Suh J. M. Kim E. Y. Dryer S. E. (2011 ). Functional NMDA receptors with atypical properties are expressed in podocytes. Am. J. Physiol. Cell. Physiol. 300 C22–C32.

    Not in our library10.1152/ajpcell.00268.2010

  7. 7.

    Andersson O. Stenqvist A. Attersand A. von Euler G. (2001 ). Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics 78 178–184.

    Not in our library10.1006/geno.2001.6666

  8. 8.

    András I. E. Deli M. A. Veszelka S. Hayashi K. Hennig B. Toborek M. (2007 ). The NMDA and AMPA KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J. Cerebr. Blood Flow Mettab. 27 1431–1443.

    Not in our library10.1038/sj.jcbfm.9600445

  9. 9.

    Antošová M. Strapková A. (2013 ). Study of the interaction of glutamatergic and nitrergic signalling in conditions of the experimental airways hyperreactivity. Pharmacol. Rep. 65 650–657.

    Not in our library10.1016/s1734-1140(13)71042-9

  10. 10.

    Avila J. Llorens-Martín M. Pallas-Bazarra N. Bolós M. Perea J. R. Rodríguez-Matellán A. (2017 ). Cognitive decline in neuronal aging and alzheimer’s disease: role of NMDA receptors and associated proteins. Front. Neurosci. 11:626

    Not in our library10.3389/fnins.2017.00626

  11. 11.

    Babiec W. E. Guglietta R. Jami S. A. Morishita W. Malenka R. C. O’Dell T. J. (2014 ). Ionotropic NMDA receptor signaling is required for the induction of long-term depression in the mouse hippocampal CA1 region. J. Neurosci. 34 5285–5290.

    Not in our library10.1523/jneurosci.5419-13.2014

  12. 12.

    Banerjee A. Larsen R. S. Philpot B. D. Paulsen O. (2016 ). Roles of presynaptic NMDA receptors in neurotransmission and plasticity. Trends Neurosci. 39 26–39.

    Not in our library10.1016/j.tins.2015.11.001

  13. 13.

    Barria A. Malinow R. (2002 ). Subunit-specific NMDA receptor trafficking to synapses. Neuron 35 345–353.

    Not in our library10.1016/s0896-6273(02)00776-6

  14. 14.

    Barria A. Malinow R. (2005 ). NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48 289–301.

    Not in our library10.1016/j.neuron.2005.08.034

  15. 15.

    Basuroy S. Leffler C. W. Parfenova H. (2013 ). CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis. Am. J. Physiol. Cell Physiol. 304 C1105–C1115.

    Not in our library10.1152/ajpcell.00023.2013

  16. 16.

    Bell K. F. S. Bennett D. A. Cuello A. C. (2007 ). Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment. J. Neurosci. 27 10810–10817.

    Not in our library10.1523/jneurosci.3269-07.2007

  17. 17.

    Benarroch E. E. (2011 ). NMDA receptors: recent insights and clinical correlations. Neurology 76 1750–1757.

    Not in our library10.1212/wnl.0b013e31821b7cc9

  18. 18.

    Bendová Z. Sumová A. Mikkelsen J. D. (2009 ). Circadian and developmental regulation of N-methyl-D-aspartate-receptor 1 mRNA splice variants and N-methyl-D-aspartate-receptor 3 subunit expression within the rat suprachiasmatic nucleus. Neuroscience 159 599–609.

    Not in our library10.1016/j.neuroscience.2009.01.016

  19. 19.

    Berg L. K. Larsson M. Morland C. Gundersen V. (2013 ). Pre- and postsynaptic localization of NMDA receptor subunits at hippocampal mossy fibre synapses. Neuroscience 230 139–150.

    Not in our library10.1016/j.neuroscience.2012.10.061

  20. 20.

    Bhattacharya S. Khatri A. Swanger S. A. DiRaddo J. O. Yi F. Hansen K. B. Yuan H. Traynelis S. F. (2018 ). Triheteromeric GluN1/GluN2A/GluN2C NMDARs with unique single-channel properties are the dominant receptor population in cerebellar granule cells. Neuron 99 315.e5–328.e5.

    Not in our library10.1016/j.neuron.2018.06.010

  21. 21.

    Bi H. Sze C. (2002 ). N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer’s disease. J. Neurol. Sci. 200 11–18.

    Not in our library10.1016/s0022-510x(02)00087-4

  22. 22.

    Bi X. Gall C. M. Zhou J. Lynch G. (2002 ). Uptake and pathogenic effects of amyloid beta peptide 1–42 are enhanced by integrin antagonists and blocked by NMDA receptor antagonists. Neuroscience 112 827–840.

    Not in our library10.1016/s0306-4522(02)00132-x

  23. 23.

    Bidoret C. Ayon A. Barbour B. Casado M. (2009 ). Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule. Proc. Natl. Acad. Sci. U.S.A. 106 14126–14131.

    Not in our library10.1073/pnas.0904284106

  24. 24.

    Binder L. I. Frankfurter A. Rebhun L. I. (1985 ). The distribution of tau in the mammalian central nervous system. J. Cell Biol. 101 1371–1378.

    Not in our library10.1083/jcb.101.4.1371

  25. 25.

    Birnbaum J. H. Bali J. Rajendran L. Nitsch R. M. Tackenberg C. (2015 ). Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss. Cell Death Dis. 6:e1791.

    Not in our library10.1038/cddis.2015.160

  26. 26.

    Bloom G. S. (2014 ). Amyloid-β and tau. JAMA Neurol. 71:505.

    Not in our library10.1001/jamaneurol.2013.5847

  27. 27.

    Bolo N. (2000 ). Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy. Neuropsychopharmacoloy 23 428–438.

    Not in our library10.1016/s0893-133x(00)00116-0

  28. 28.

    Bonuccelli U. Del Dotto P. (2006 ). New pharmacologic horizons in the treatment of Parkinson disease. Neurology 67 S30–S38.

    Not in our library10.1212/wnl.67.7_suppl_2.s30

  29. 29.

    Bordji K. Becerril-Ortega J. Nicole O. Buisson A. (2010 ). Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production. J. Neurosci. 30 15927–15942.

    Not in our library10.1523/jneurosci.3021-10.2010

  30. 30.

    Bouvier G. Bidoret C. Casado M. Paoletti P. (2015 ). Presynaptic NMDA receptors: roles and rules. Neuroscience 311 322–340.

    Not in our library10.1016/j.neuroscience.2015.10.033

  31. 31.

    Bouvier G. Larsen R. S. Rodríguez-Moreno A. Paulsen O. Sjöström P. J. (2018 ). Towards resolving the presynaptic NMDA receptor debate. Curr. Opin. Neurobiol. 51 1–7.

    Not in our library10.1016/j.conb.2017.12.020

  32. 32.

    Brasier D. J. Feldman D. E. (2008 ). Synapse-specific expression of functional presynaptic NMDA receptors in rat somatosensory cortex. J. Neurosci. 28 2199–2211.

    Not in our library10.1523/jneurosci.3915-07.2008

  33. 33.

    Bu G. Cam J. Zerbinatti C. (2006 ). LRP in amyloid-beta production and metabolism. Ann. N. Y. Acad. Sci. 1086 35–53.

    Not in our library10.1196/annals.1377.005

  34. 34.

    Burzomato V. Frugier G. Pérez-Otaño I. Kittler J. T. Attwell D. (2010 ). The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes. J. Physiol. 588 3403–3414.

    Not in our library10.1113/jphysiol.2010.195503

  35. 35.

    Busciglio J. Gabuzda D. H. Matsudaira P. Yankner B. A. (1993 ). Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc. Natl. Acad. Sci. U.S.A. 90 2092–2096.

    Not in our library10.1073/pnas.90.5.2092

  36. 36.

    Caldeira G. L. Ferreira I. L. Rego A. C. (2013 ). Impaired transcription in Alzheimer’s disease: key role in mitochondrial dysfunction and oxidative stress. J. Alzheimers Dis. 34 115–131.

    Not in our library10.3233/jad-121444

  37. 37.

    Camandola S. Mattson M. P. (2011 ). Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. BBA-Mol. Cell Res. 1813 965–973.

    Not in our library10.1016/j.bbamcr.2010.10.005

  38. 38.

    Carter B. C. Jahr C. E. (2016 ). Postsynaptic, not presynaptic NMDA receptors are required for spike-timing-dependent LTD induction. Nat. Neurosci. 19 1218–1224.

    Not in our library10.1038/nn.4343

  39. 39.

    Casas-Tinto S. Zhang Y. Sanchez-Garcia J. Gomez-Velazquez M. Rincon-Limas D. E. Fernandez-Funez P. (2011 ). The ER stress factor XBP1s prevents amyloid-β neurotoxicity. Hum. Mol. Genet. 20 2144–2160.

    Not in our library10.1093/hmg/ddr100

  40. 40.

    Cavara N. A. Orth A. Hicking G. Seebohm G. Hollmann M. (2010 ). Residues at the tip of the pore loop of NR3B-containing NMDA receptors determine Ca2+ permeability and Mg2+ block. BMC Neurosci. 11:133.

    Not in our library10.1186/1471-2202-11-133

  41. 41.

    Chang L. Zhang Y. Liu J. Song Y. Lv A. Li Y. (2016 ). Differential regulation of N-methyl-D-aspartate receptor subunits is an early events in the actions of soluble amyloid-β1-40 oligomers on hippocampal neurons. J. Alzheimers Dis. 51 197–212.

    Not in our library10.3233/jad-150942

  42. 42.

    Chatterton J. E. Awobuluyi M. Premkumar L. S. Takahashi H. Talantova M. Shin Y. (2002 ). Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415 793–798.

    Not in our library10.1038/nature715

  43. 43.

    Chen N. Moshaver A. Raymond L. A. (1997 ). Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition. Mol. Pharmacol. 51:1015

    Not in our library10.1124/mol.51.6.1015

  44. 44.

    Chen Q. Zhou Z. Zhang L. Wang Y. Zhang Y. Zhong M. (2012 ). Tau protein is involved in morphological plasticity in hippocampal neurons in response to BDNF. Neurochem. Int. 60 233–242.

    Not in our library10.1016/j.neuint.2011.12.013

  45. 45.

    Chenard B. L. Bordner J. Butler T. W. Chambers L. K. Collins M. A. De Costa D. L. (1995 ). (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-Methyl-D-aspartate responses. J. Med. Chem. 38 3138–3145.

    Not in our library10.1021/jm00016a017

  46. 46.

    Choi D. W. (1987 ). Ionic dependence of glutamate neurotoxicity. J. Neurosci. 7 369–379.

    Not in our library10.1523/jneurosci.07-02-00369.1987

  47. 47.

    Choi D. W. (1988 ). Glutamate neurotoxicity and diseases of the nervous system. Neuron 1 623–634.

    Not in our library10.1016/0896-6273(88)90162-6

  48. 48.

    Choi D. W. (1992 ). Excitotoxic cell death. J. Neurobiol. 23 1261–1276.

    Not in our library10.1002/neu.480230915

  49. 49.

    Choi D. W. Koh J. Y. Peters S. (1988 ). Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J. Neurosci. 8 185–196.

    Not in our library10.1523/jneurosci.08-01-00185.1988

  50. 50.

    Chung C. (2013 ). NMDA receptor as a newly identified member of the metabotropic glutamate receptor family: clinical implications for neurodegenerative diseases. Mol. Cells 36 99–104.

    Not in our library10.1007/s10059-013-0113-y

  51. 51.

    Ciabarra A. M. Sullivan J. M. Gahn L. G. Pecht G. Heinemann S. Sevarino K. A. (1995 ). Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J. Neurosci. 15 6498–6508.

    Not in our library10.1523/jneurosci.15-10-06498.1995

  52. 52.

    Cirrito J. R. Yamada K. A. Finn M. B. Sloviter R. S. Bales K. R. May P. C. (2005 ). Synaptic activity regulates interstitial fluid Amyloid-β levels in vivo. Neuron 48 913–922.

    Not in our library10.1016/j.neuron.2005.10.028

  53. 53.

    Cleary J. P. Walsh D. M. Hofmeister J. J. Shankar G. M. Kuskowski M. A. Selkoe D. J. (2005 ). Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat. Neurosci. 8 79–84.

    Not in our library10.1038/nn1372

  54. 54.

    Cook D. G. Forman M. S. Sung J. C. Leight S. Kolson D. L. Iwatsubo T. (1997 ). Alzheimer’s A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat. Med. 3 1021–1023.

    Not in our library10.1038/nm0997-1021

  55. 55.

    Corlew R. Wang Y. Ghermazien H. Erisir A. Philpot B. D. (2007 ). Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. J. Neurosci. 27 9835–9845.

    Not in our library10.1523/jneurosci.5494-06.2007

  56. 56.

    Costa R. O. Lacor P. N. Ferreira I. L. Resende R. Auberson Y. P. Klein W. L. (2012 ). Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-D-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers. Aging Cell 11 823–833.

    Not in our library10.1111/j.1474-9726.2012.00848.x

  57. 57.

    Cull-Candy S. Brickley S. Farrant M. (2001 ). NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11 327–335.

    Not in our library10.1016/s0959-4388(00)00215-4

  58. 58.

    Dalva M. B. Takasu M. A. Lin M. Z. Shamah S. M. Hu L. Gale N. W. (2000 ). EphB Receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103 945–956.

    Not in our library10.1016/s0092-8674(00)00197-5

  59. 59.

    Danysz W. Parsons C. G. (2003 ). The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int. J. Geriatr. Psychol. 18 S23–S32.

    Not in our library10.1002/gps.938

  60. 60.

    Danysz W. Parsons C. G. (2012 ). Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine – Searching for the connections. Br. J. Pharmacol. 167 324–352.

    Not in our library10.1111/j.1476-5381.2012.02057.x

  61. 61.

    De Felice F. G. Velasco P. T. Lambert M. P. Viola K. Fernandez S. J. Ferreira S. T. (2007 ). Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 282 11590–11601.

    Not in our library10.1074/jbc.m607483200

  62. 62.

    Deane R. Du Yan S. Submamaryan R. K. LaRue B. Jovanovic S. Hogg E. (2003 ). RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat. Med. 9 907–913.

    Not in our library10.1038/nm890

  63. 63.

    Deardorff W. J. Grossberg G. T. (2016 ). Pharmacotherapeutic strategies in the treatment of severe Alzheimer’s disease. Expert Opin. Pharmacother. 17 1789–1800.

    Not in our library10.1080/14656566.2016.1215431

  64. 64.

    Decker J. M. Krüger L. Sydow A. Dennissen F. J. Siskova Z. Mandelkow E. (2016 ). The Tau/A152T mutation, a risk factor for frontotemporal-spectrum disorders, leads to NR2B receptor-mediated excitotoxicity. EMBO Rep. 17 552–569.

    Not in our library10.15252/embr.201541439

  65. 65.

    Delacourte A. Flament S. Dibe E. M. Hublau P. Sablonnière B. Hémon B. (1990 ). Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer’s disease. Acta Neuropathol. 80 111–117.

    Not in our library10.1007/bf00308912

  66. 66.

    Deng A. Thomson S. C. (2009 ). Renal NMDA receptors independently stimulate proximal reabsorption and glomerular filtration. Am. J. Physiol. Renal Physiol. 296 976–982.

    Not in our library10.1152/ajprenal.90391.2008

  67. 67.

    Dineley K. T. Bell K. A. Bui D. Sweatt J. D. (2002 ). β-amyloid peptide activates α7 nicotinic acetylcholine receptors expressed in xenopus oocytes. J. Biol. Chem. 277 25056–25061.

    Not in our library10.1074/jbc.m200066200

  68. 68.

    Domingues A. Almeida S. Da C. E. S. E. Oliveira C. R. Rego A. C. (2007 ). Toxicity of beta-amyloid in HEK293 cells expressing NR1/NR2A or NR1/NR2B N-methyl-D-aspartate receptor subunits. Neurochem. Int. 50 872–880.

    Not in our library10.1016/j.neuint.2007.03.001

  69. 69.

    Dore K. Stein I. S. Brock J. A. Castillo P. E. Zito K. Sjöström P. J. (2017 ). unconventional NMDA receptor signaling. J. Neurosci. 37 10800–10807.

    Not in our library10.1523/jneurosci.1825-17.2017

  70. 70.

    Duguid I. C. (2013 ). Presynaptic NMDA receptors: are they dendritic receptors in disguise? Brain Res. Bull. 93 4–9.

    Not in our library10.1016/j.brainresbull.2012.12.004

  71. 71.

    Dunah A. W. Luo J. Wang Y. H. Yasuda R. P. Wolfe B. B. (1998 ). Subunit composition of N-methyl-D-aspartate receptors in the central nervous system that contain the NR2D subunit. Mol. Pharmacol. 53 429–437.

    Not in our library10.1124/mol.53.3.429

  72. 72.

    Dzamba D. Honsa P. Anderova M. (2013 ). NMDA receptors in glial cells: pending questions. Curr. Neuropharmacol. 11 250–262.

    Not in our library10.2174/1570159x11311030002

  73. 73.

    Ellison G. (1995 ). The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res. Brain Res. Rev. 20 250–267.

    Not in our library10.1016/0165-0173(94)00014-g

  74. 74.

    Epstein F. H. Lipton S. A. Rosenberg P. A. (1994 ). Excitatory amino acids as a final common pathway for neurologic disorders. New Engl. J. Med. 330 613–622.

    Not in our library10.1056/nejm199403033300907

  75. 75.

    Erreger K. Dravid S. M. Banke T. G. Wyllie D. J. A. Traynelis S. F. (2005 ). Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J. Physiol. 563 345–358.

    Not in our library10.1113/jphysiol.2004.080028

  76. 76.

    Esclaire F. O. Lesort M. Blanchard C. Hugon J. (1997 ). Glutamate toxicity enhances tau gene expression in neuronal cultures. J. Neurosci. Res. 49 309–318.

    Not in our library10.1002/(sici)1097-4547(19970801)49:3<309::aid-jnr6<3.0.co;2-g

  77. 77.

    Fan M. Raymond L. (2007 ). N-Methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog. Neurobiol. 81 272–293.

    Not in our library10.1016/j.pneurobio.2006.11.003

  78. 78.

    Farinelli M. Heitz F. D. Grewe B. F. Tyagarajan S. K. Helmchen F. Mansuy I. M. (2012 ). Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. PLoS One 7:e34047.

    Not in our library10.1371/journal.pone.0034047

  79. 79.

    Fellin T. Pascual O. Gobbo S. Pozzan T. Haydon P. G. Carmignoto G. (2004 ). Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43 729–743.

    Not in our library10.1016/j.neuron.2004.08.011

  80. 80.

    Fernandes A. Wojcik T. Baireddy P. Pieschl R. Newton A. Tian Y. (2015 ). Inhibition of in vivo [3H]MK-801 binding by NMDA receptor open channel blockers and GluN2B antagonists in rats and mice. Eur. J. Pharmacol. 766 1–8.

    Not in our library10.1016/j.ejphar.2015.08.044

  81. 81.

    Ferreira I. L. Bajouco L. M. Mota S. I. Auberson Y. P. Oliveira C. R. Rego A. C. (2012 ). Amyloid beta peptide 1–42 disturbs intracellular calcium homeostasis through activation of GluN2B-containing N-methyl-D-aspartate receptors in cortical cultures. Cell Calcium 51 95–106.

    Not in our library10.1016/j.ceca.2011.11.008

  82. 82.

    Ferreira I. L. Ferreiro E. Schmidt J. Cardoso J. M. Pereira C. M. F. Carvalho A. L. (2015 ). Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release. Neurobiol. Aging 36 680–692.

    Not in our library10.1016/j.neurobiolaging.2014.09.006

  83. 83.

    Ferreira I. L. Resende R. Ferreiro E. Rego A. C. Pereira C. F. (2010 ). Multiple defects in energy metabolism in Alzheimer’s disease. Curr. Drug Targets 11:1193

    Not in our library10.2174/1389450111007011193

  84. 84.

    Fischer G. Mutel V. Trube G. Malherbe P. Kew J. N. Mohacsi E. (1997 ). Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit, characterization in vitro. J. Pharmacol. Exp. Ther. 283 1285–1292.

    Not in our library

  85. 85.

    Fonseca A. C. R. G. Ferreiro E. Oliveira C. R. Cardoso S. M. Pereira C. F. (2013 ). Activation of the endoplasmic reticulum stress response by the amyloid-beta 1–40 peptide in brain endothelial cells. BBA-Mol. Basis Dis. 1832 2191–2203.

    Not in our library10.1016/j.bbadis.2013.08.007

  86. 86.

    Foster T. C. Kyritsopoulos C. Kumar A. (2017 ). Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease. Behav. Brain Res. 322 223–232.

    Not in our library10.1016/j.bbr.2016.05.012

  87. 87.
    Efficacy of Memantine for Agitation in Alzheimer’s Dementia: A Randomised Double-Blind Placebo Controlled Trial · 2012
    No notice
  88. 88.

    Franco R. Aguinaga D. Reyes I. Canela E. I. Lillo J. Tarutani A. (2018 ). N-Methyl-D-aspartate receptor link to the MAP kinase pathway in cortical and hippocampal neurons and microglia is dependent on calcium sensors and is blocked by α-synuclein, tau, and phospho-tau in non-transgenic and transgenic APPSw, ind mice. Front. Mol. Neurosci. 11:273.

    Not in our library10.3389/fnmol.2018.00273

  89. 89.

    Gerard F. Hansson E. (2012 ). Inflammatory activation enhances NMDA-triggered Ca2+ signalling and IL-1beta secretion in primary cultures of rat astrocytes. Brain Res. 1473 1–8.

    Not in our library10.1016/j.brainres.2012.07.032

  90. 90.

    Glabe C. G. (2008 ). Structural classification of toxic amyloid oligomers. J. Biol. Chem. 283 29639–29643.

    Not in our library10.1074/jbc.r800016200

  91. 91.

    Gladding C. M. Raymond L. A. (2011 ). Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol. Cell Neurosci. 48 308–320.

    Not in our library10.1016/j.mcn.2011.05.001

  92. 92.

    Graef J. D. Newberry K. Newton A. Pieschl R. Shields E. Luan F. (2015 ). Effect of acute NR2B antagonist treatment on long-term potentiation in the rat hippocampus. Brain Res. 1609 31–39.

    Not in our library10.1016/j.brainres.2015.03.019

  93. 93.

    Graham W. V. Bonito-Oliva A. Sakmar T. P. (2017 ). Update on Alzheimer’s disease therapy and prevention strategies. Annu. Rev. Med. 68 413–430.

    Not in our library10.1146/annurev-med-042915-103753

  94. 94.

    Groc L. Choquet D. Stephenson F. A. Verrier D. Manzoni O. J. Chavis P. (2007 ). NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein reelin. J. Neurosci. 27 10165–10175.

    Not in our library10.1523/jneurosci.1772-07.2007

  95. 95.

    Groc L. Heine M. Cousins S. L. Stephenson F. A. Lounis B. Cognet L. (2006 ). NMDA receptor surface mobility depends on NR2A-2B subunits. Proc. Natl. Acad. Sci. U.S.A. 103 18769–18774.

    Not in our library10.1073/pnas.0605238103

  96. 96.

    Grochowska K. M. Yuanxiang P. Bär J. Raman R. Brugal G. Sahu G. (2017 ). Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction. EMBO Rep. 18 962–981.

    Not in our library10.15252/embr.201643519

  97. 97.

    Grothe M. J. Barthel H. Sepulcre J. Dyrba M. Sabri O. Teipel S. J. (2017 ). In vivo staging of regional amyloid deposition. Neurology 89 2031–2038.

    Not in our library10.1212/wnl.0000000000004643

  98. 98.

    Groveman B. R. Feng S. Fang X. Pflueger M. Lin S. Bienkiewicz E. A. (2012 ). The regulation of N-methyl-D-aspartate receptors by Src kinase. FEBS J. 279 20–28.

    Not in our library10.1111/j.1742-4658.2011.08413.x

  99. 99.

    Haas L. T. Kostylev M. A. Strittmatter S. M. (2014 ). Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). J. Biol. Chem. 289 28460–28477.

    Not in our library10.1074/jbc.m114.584342

  100. 100.

    Hackos D. H. Hanson J. E. (2017 ). Diverse modes of NMDA receptor positive allosteric modulation: mechanisms and consequences. Neuropharmacology 112 34–45.

    Not in our library10.1016/j.neuropharm.2016.07.037

  101. 101.

    Haghikia A. Mergia E. Friebe A. Eysel U. T. Koesling D. Mittmann T. (2007 ). Long-term potentiation in the visual cortex requires both nitric oxide receptor guanylyl cyclases. J. Neurosci. 27 818–823.

    Not in our library10.1523/jneurosci.4706-06.2007

  102. 102.

    Hamilton N. B. Kolodziejczyk K. Kougioumtzidou E. Attwell D. (2016 ). Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 529 523–527.

    Not in our library10.1038/nature16519

  103. 103.

    Hansen K. B. Ogden K. K. Yuan H. Traynelis S. F. (2014 ). Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors. Neuron 81 1084–1096.

    Not in our library10.1016/j.neuron.2014.01.035

  104. 104.

    Hansson Petersen C. A. Alikhani N. Behbahani H. Wiehager B. Pavlov P. F. Alafuzoff I. (2008 ). The amyloid -peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl. Acad. Sci. U.S.A. 105 13145–13150.

    Not in our library10.1073/pnas.0806192105

  105. 105.

    Hardingham G. E. Bading H. (2010 ). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat. Rev. Neurosci. 11 682–696.

    Not in our library10.1038/nrn2911

  106. 106.

    Hardingham G. E. Fukunaga Y. Bading H. (2002 ). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5 405–414.

    Not in our library10.1038/nn835

  107. 107.

    Hardy J. (2002 ). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297 353–356.

    Not in our library10.1126/science.1072994

  108. 108.

    Harris A. Z. Pettit D. L. (2007 ). Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices. J. Physiol. 584 509–519.

    Not in our library10.1113/jphysiol.2007.137679

  109. 109.

    Harris A. Z. Pettit D. L. (2008 ). Recruiting extrasynaptic NMDA receptors augments synaptic signaling. J. Neurophysiol. 99 524–533.

    Not in our library10.1152/jn.01169.2007

  110. 110.

    Hartmann T. Bieger S. C. Brühl B. Tienari P. J. Ida N. Allsop D. (1997 ). Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat. Med. 3:1016

    Not in our library10.1038/nm0997-1016

  111. 111.

    Hatton C. J. Paoletti P. (2005 ). Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron 46 261–274.

    Not in our library10.1016/j.neuron.2005.03.005

  112. 112.

    Hell J. W. Gray J. A. Zito K. (2016 ). Non-ionotropic signaling by the NMDA receptor: controversy and opportunity. F1000Res. 5:1010.

    Not in our library10.12688/f1000research.8366.1

  113. 113.

    Henson M. A. Larsen R. S. Lawson S. N. Pérez-Otaño I. Nakanishi N. Lipton S. A. (2012 ). Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS One 7:e42327.

    Not in our library10.1371/journal.pone.0042327

  114. 114.

    Henson M. A. Roberts A. C. Pérez-Otaño I. Philpot B. D. (2010 ). Influence of the NR3A subunit on NMDA receptor functions. Prog. Neurobiol. 91 23–37.

    Not in our library10.1016/j.pneurobio.2010.01.004

  115. 115.

    Herman M. A. Jahr C. E. (2007 ). Extracellular glutamate concentration in hippocampal slice. J. Neurosci. 27 9736–9741.

    Not in our library10.1523/jneurosci.3009-07.2007

  116. 116.

    Hinoi E. Fujimori S. Yoneda Y. (2003 ). Modulation of cellular differentiation by N-methyl-D-aspartate receptors in osteoblasts. FASEB J. 17 1532–1534.

    Not in our library10.1096/fj.02-0820fje

  117. 117.

    Hoey S. E. Williams R. J. Perkinton M. S. (2009 ). Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J. Neurosci. 29 4442–4460.

    Not in our library10.1523/jneurosci.6017-08.2009

  118. 118.

    Hogan-Cann A. D. Anderson C. M. (2016 ). Physiological roles of non-neuronal NMDA receptors. Trends Pharmacol. Sci. 37 750–767.

    Not in our library10.1016/j.tips.2016.05.012

  119. 119.

    Hsieh H. Boehm J. Sato C. Iwatsubo T. Tomita T. Sisodia S. (2006 ). AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52 831–843.

    Not in our library10.1016/j.neuron.2006.10.035

  120. 120.

    Hunter S. Smailagic N. Brayne C. (2018 ). Aβ and the dementia syndrome: simple versus complex perspectives. Eur. J. Clin. Invest. 48:e13025.

    Not in our library10.1111/eci.13025

  121. 121.

    Hynd M. R. Scott H. L. Dodd P. R. (2001 ). Glutamate(NMDA) receptor NR1 subunit mRNA expression in Alzheimer’s disease. J. Neurochem. 78:175

    Not in our library10.1046/j.1471-4159.2001.00409.x

  122. 122.

    Hynd M. R. Scott H. L. Dodd P. R. (2004 ). Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer’s disease. J. Neurochem. 90 913–919.

    Not in our library10.1111/j.1471-4159.2004.02548.x

  123. 123.

    Inagaki N. Kuromi H. Gonoi T. Okamoto Y. Ishida H. Seino Y. (1995 ). Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB J. 9 686–691.

    Not in our library10.1096/fasebj.9.8.7768362

  124. 124.

    Ittner L. M. Ke Y. D. Delerue F. Bi M. Gladbach A. van Eersel J. (2010 ). Dendritic function of tau mediates amyloid-β toxicity in alzheimer’s disease mouse models. Cell 142 387–397.

    Not in our library10.1016/j.cell.2010.06.036

  125. 125.

    Jacob C. P. Koutsilieri E. Bartl J. Neuen-Jacob E. Arzberger T. Zander N. (2007 ). Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J. Alzheimers Dis. 11 97–116.

    Not in our library10.3233/jad-2007-11113

  126. 126.

    Jagust W. (2018 ). Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 19 687–700.

    Not in our library10.1038/s41583-018-0067-3

  127. 127.

    Jimenez-Blasco D. Santofimia-Castaño P. Gonzalez A. Almeida A. Bolaños J. P. (2015 ). Astrocyte NMDA receptors’ activity sustains neuronal survival through a Cdk5–Nrf2 pathway. Cell Death Differ. 22 1877–1889.

    Not in our library10.1038/cdd.2015.49

  128. 128.

    Jourdain P. Bergersen L. H. Bhaukaurally K. Bezzi P. Santello M. Domercq M. (2007 ). Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10 331–339.

    Not in our library10.1038/nn1849

  129. 129.

    Kaindl A. M. Degos V. Peineau S. Gouadon E. Chhor V. Loron G. (2012 ). Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann. Neurol. 72 536–549.

    Not in our library10.1002/ana.23626

  130. 130.

    Kamenetz F. Tomita T. Hsieh H. Seabrook G. Borchelt D. Iwatsubo T. (2003 ). APP processing and synaptic function. Neuron 37 925–937.

    Not in our library10.1016/s0896-6273(03)00124-7

  131. 131.

    Káradóttir R. Cavelier P. Bergersen L. H. Attwell D. (2005 ). NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438 1162–1166.

    Not in our library10.1038/nature04302

  132. 132.

    Karakas E. Furukawa H. (2014 ). Crystal structure of a heterotetrameric NMDA receptor ion channel. Science 344 992–997.

    Not in our library10.1126/science.1251915

  133. 133.

    Kato H. Narita M. Miyatake M. Yajima Y. Suzuki T. (2006 ). Role of neuronal NR2B subunit-containing NMDA receptor-mediated Ca2+ influx and astrocytic activation in cultured mouse cortical neurons and astrocytes. Synapse 59 10–17.

    Not in our library10.1002/syn.20213

  134. 134.

    Kavalali E. T. (2015 ). The mechanisms and functions of spontaneous neurotransmitter release. Nat. Rev. Neurosci. 16 5–16.

    Not in our library10.1038/nrn3875

  135. 135.

    Kessels H. W. Nabavi S. Malinow R. (2013 ). Metabotropic NMDA receptor function is required for -amyloid-induced synaptic depression. Proc. Natl. Acad. Sci. U.S.A. 110 4033–4038.

    Not in our library10.1073/pnas.1219605110

  136. 136.

    Khoury R. Patel K. Gold J. Hinds S. Grossberg G. T. (2017 ). Recent progress in the pharmacotherapy of Alzheimer’s disease. Drug Aging 34 811–820.

    Not in our library10.1007/s40266-017-0499-x

  137. 137.

    Kim J. Anwyl R. Suh Y. Djamgoz M. B. A. Rowan M. J. (2001 ). Use-dependent effects of amyloidogenic fragments of {beta}-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J. Neurosci. 21 1327–1333.

    Not in our library10.1523/jneurosci.21-04-01327.2001

  138. 138.

    Kim J. H. Liao D. Lau L. Huganir R. L. (1998 ). SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20 683–691.

    Not in our library10.1016/s0896-6273(00)81008-9

  139. 139.
    Microtubule-associated protein tau is essential for long-term depression in the hippocampus · 2014
    No notice
  140. 140.

    Kinoshita A. (2003 ). Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J. Cell Sci. 116 3339–3346.

    Not in our library10.1242/jcs.00643

  141. 141.

    Kiss J. P. Szasz B. K. Fodor L. Mike A. Lenkey N. Kurkó D. (2012 ). GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine. Neurochem. Int. 60 170–176.

    Not in our library10.1016/j.neuint.2011.12.005

  142. 142.

    Kodis E. J. Choi S. Swanson E. Ferreira G. Bloom G. S. (2018 ). N-methyl-D-aspartate receptor-mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer’s disease. Alzheimers Dement. 14 1302–1312.

    Not in our library10.1016/j.jalz.2018.05.017

  143. 143.

    Köhr G. (2006 ). NMDA receptor function: subunit composition versus spatial distribution. Cell Tissue Res. 326 439–446.

    Not in our library10.1007/s00441-006-0273-6

  144. 144.

    Köhr G. (2007 ). NMDA receptor mobility: cultures versus acute brain slices or neonatalversus mature synapses? J. Physiol. 584 367–367.

    Not in our library10.1113/jphysiol.2007.144865

  145. 145.

    Kong M. Ba M. Liu C. Zhang Y. Zhang H. Qiu H. (2015 ). NR2B antagonist CP-101,606 inhibits NR2B phosphorylation at tyrosine-1472 and its interactions with Fyn in levodopa-induced dyskinesia rat model. Behav. Brain Res. 282 46–53.

    Not in our library10.1016/j.bbr.2014.12.059

  146. 146.

    Krapivinsky G. Krapivinsky L. Manasian Y. Ivanov A. Tyzio R. Pellegrino C. (2003 ). The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 40 775–784.

    Not in our library10.1016/s0896-6273(03)00645-7

  147. 147.

    Kullmann D. M. Lamsa K. P. (2007 ). Long-term synaptic plasticity in hippocampal interneurons. Nat. Rev. Neurosci. 8 687–699.

    Not in our library10.1038/nrn2207

  148. 148.

    Kunz P. A. Roberts A. C. Philpot B. D. (2013 ). Presynaptic NMDA receptor mechanisms for enhancing spontaneous neurotransmitter release. J. Neurosci. 33 7762–7769.

    Not in our library10.1523/jneurosci.2482-12.2013

  149. 149.

    Kurup P. Zhang Y. Xu J. Venkitaramani D. V. Haroutunian V. Greengard P. (2010 ). Abeta-mediated NMDA receptor endocytosis in Alzheimer’s disease involves ubiquitination of the tyrosine phosphatase STEP61. J. Neurosci. 30 5948–5957.

    Not in our library10.1523/jneurosci.0157-10.2010

  150. 150.

    Kvist T. Greenwood J. R. Hansen K. B. Traynelis S. F. Bräuner-Osborne H. (2013 ). Structure-based discovery of antagonists for GluN3-containing N-methyl-D-aspartate receptors. Neuropharmacology 75 324–336.

    Not in our library10.1016/j.neuropharm.2013.08.003

  151. 151.

    Lacor P. N. Buniel M. C. Furlow P. W. Clemente A. S. Velasco P. T. Wood M. (2007 ). Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J. Neurosci. 27 796–807.

    Not in our library10.1523/jneurosci.3501-06.2007

  152. 152.

    LaFerla F. M. Green K. N. Oddo S. (2007 ). Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neurosci. 8 499–509.

    Not in our library10.1038/nrn2168

  153. 153.

    Lalo U. (2006 ). NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J. Neurosci. 26 2673–2683.

    Not in our library10.1523/jneurosci.4689-05.2006

  154. 154.

    Larsen R. S. Corlew R. J. Henson M. A. Roberts A. C. Mishina M. Watanabe M. (2011 ). NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat. Neurosci. 14 338–344.

    Not in our library10.1038/nn.2750

  155. 155.

    Larsen R. S. Smith I. T. Miriyala J. Han J. E. Corlew R. J. Smith S. L. (2014 ). Synapse-specific control of experience-dependent plasticity by presynaptic NMDA receptors. Neuron 83 879–893.

    Not in our library10.1016/j.neuron.2014.07.039

  156. 156.

    Lau C. G. Takeuchi K. Rodenas-Ruano A. Takayasu Y. Murphy J. Bennett M. V. L. (2009 ). Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem. Soc. Trans. 37 1369–1374.

    Not in our library10.1042/bst0371369

  157. 157.

    Lazarov O. Lee M. Peterson D. A. Sisodia S. S. (2002 ). Evidence that synaptically released β-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J. Neurosci. 22 9785–9793.

    Not in our library10.1523/jneurosci.22-22-09785.2002

  158. 158.

    Lee C. Lü W. Michel J. C. Goehring A. Du J. Song X. (2014 ). NMDA receptor structures reveal subunit arrangement and pore architecture. Nature 511 191–197.

    Not in our library10.1038/nature13548

  159. 159.

    Lee G. (2004 ). Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J. Neurosci. 24 2304–2312.

    Not in our library10.1523/jneurosci.4162-03.2004

  160. 160.

    Lee G. Newman S. T. Gard D. L. Band H. Panchamoorthy G. (1998 ). Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 111(Pt 21), 3167.

    Not in our library10.1242/jcs.111.21.3167

  161. 161.
    Characterisation of the Expression of NMDA Receptors in Human Astrocytes · 2010
    No notice
  162. 162.

    Lesne S. (2005 ). NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid- production. J. Neurosci. 25 9367–9377.

    Not in our library10.1523/jneurosci.0849-05.2005

  163. 163.

    Leveille F. El G. F. Gouix E. Lecocq M. Lobner D. Nicole O. (2008 ). Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J. 22 4258–4271.

    Not in our library10.1096/fj.08-107268

  164. 164.

    Li C. Xiao L. Liu X. Yang W. Shen W. Hu C. (2013 ). A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination. Glia 61 732–749.

    Not in our library10.1002/glia.22469

  165. 165.

    Li J. Zhao L. Cui B. Deng L. Ning G. Liu J. (2011 ). Multiple signaling pathways involved in stimulation of osteoblast differentiation by N-methyl-D-aspartate receptors activation in vitro. Acta Pharmacol. Sin. 32 895–903.

    Not in our library10.1038/aps.2011.38

  166. 166.

    Li S. Hong S. Shepardson N. E. Walsh D. M. Shankar G. M. Selkoe D. (2009 ). Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62 788–801.

    Not in our library10.1016/j.neuron.2009.05.012

  167. 167.

    Li Y. Chang L. Song Y. Gao X. Roselli F. Liu J. (2016 ). Astrocytic GluN2A and GluN2B oppose the synaptotoxic effects of amyloid-β1-40 in hippocampal cells. J. Alzheimers Dis. 54 135–148.

    Not in our library10.3233/jad-160297

  168. 168.

    Lipton S. A. (2006 ). Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discov. 5 160–170.

    Not in our library10.1038/nrd1958

  169. 169.

    Liu B. Zhu Y. Zhou J. Wei Y. Long C. Chen M. (2014 ). Endoplasmic reticulum stress promotes amyloid-beta peptides production in RGC-5 cells. Cell Stress Chaperones 19 827–835.

    Not in our library10.1007/s12192-014-0506-7

  170. 170.

    Liu J. Chang L. Roselli F. Almeida O. F. X. Gao X. Wang X. (2010 ). Amyloid-β induces caspase-dependent loss of PSD-95 and synaptophysin through NMDA receptors. J. Alzheimers Dis. 22 541–556.

    Not in our library10.3233/jad-2010-100948

  171. 171.

    Liu L. (2004 ). Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304 1021–1024.

    Not in our library10.1126/science.1096615

  172. 172.

    Liu S. B. Zhang N. Guo Y. Y. Zhao R. Shi T. Y. Feng S. F. (2012 ). G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors. J. Neurosci. 32 4887–4900.

    Not in our library10.1523/jneurosci.5828-11.2012

  173. 173.

    Liu Y. Wong T. P. Aarts M. Rooyakkers A. Liu L. Lai T. W. (2007 ). NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27 2846–2857.

    Not in our library10.1523/jneurosci.0116-07.2007

  174. 174.

    Low C. M. Wee K. S. L. (2010 ). New insights into the not-so-new nr3 subunits of n-methyl-D-aspartate receptor: localization, structure, and function. Mol. Pharmacol. 78 1–11.

    Not in our library10.1124/mol.110.064006

  175. 175.

    Luscher C. Malenka R. C. (2012 ). NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). Cold Spring Perspect. Biol. 4:a005710.

    Not in our library10.1101/cshperspect.a005710

  176. 176.

    Lynch G. Larson J. Kelso S. Barrionuevo G. Schottler F. (1983 ). Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305 719–721.

    Not in our library10.1038/305719a0

  177. 177.

    MacDermott A. B. Mayer M. L. Westbrook G. L. Smith S. J. Barker J. L. (1986 ). NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321 519–522.

    Not in our library10.1038/321519a0

  178. 178.

    MacDonald J. F. Jackson M. F. Beazely M. A. (2006 ). Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Crit. Rev. Neurobiol. 18 71–84.

    Not in our library10.1615/critrevneurobiol.v18.i1-2.80

  179. 179.

    Maeda S. Djukic B. Taneja P. Yu G. Q. Lo I. Davis A. (2016 ). Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. EMBO Rep. 17 530–551.

    Not in our library10.15252/embr.201541438

  180. 180.

    Malenka R. C. (1994 ). Synaptic plasticity in the hippocampus: LTP and LTD. Cell 78 535–538.

    Not in our library10.1016/0092-8674(94)90517-7

  181. 181.

    Malenka R. C. Bear M. F. (2004 ). LTP and LTD: an embarrassment of riches. Neuron 44 5–21.

    Not in our library10.1016/j.neuron.2004.09.012

  182. 182.

    Malinow R. (2012 ). New developments on the role of NMDA receptors in Alzheimer’s disease. Curr. Opin. Neurobiol. 22 559–563.

    Not in our library10.1016/j.conb.2011.09.001

  183. 183.

    Manczak M. Anekonda T. S. Henson E. Park B. S. Quinn J. Reddy P. H. (2006 ). Mitochondria are a direct site of Aβ accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 15 1437–1449.

    Not in our library10.1093/hmg/ddl066

  184. 184.

    Marquard J. Otter S. Welters A. Stirban A. Fischer A. Eglinger J. (2015 ). Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat. Med. 21 363–372.

    Not in our library10.1038/nm.3822

  185. 185.

    Martel M. A. Wyllie D. J. A. Hardingham G. E. (2009 ). In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death. Neuroscience 158 334–343.

    Not in our library10.1016/j.neuroscience.2008.01.080

  186. 186.

    Martínez-Turrillas R. Puerta E. Chowdhury D. Marco S. Watanabe M. Aguirre N. (2012 ). The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation. Neurobiol. Dis. 48 290–298.

    Not in our library10.1016/j.nbd.2012.07.001

  187. 187.

    Massey P. V. (2004 ). Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J. Neurosci. 24 7821–7828.

    Not in our library10.1523/jneurosci.1697-04.2004

  188. 188.

    Matsuda K. Fletcher M. Kamiya Y. Yuzaki M. (2003 ). Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J. Neurosci. 23 10064–10073.

    Not in our library10.1523/jneurosci.23-31-10064.2003

  189. 189.

    Mayer M. L. Westbrook G. L. Guthrie P. B. (1984 ). Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309 261–263.

    Not in our library10.1038/309261a0

  190. 190.

    McGuinness L. Taylor C. Taylor R. D. T. Yau C. Langenhan T. Hart M. L. (2010 ). Presynaptic NMDARs in the hippocampus facilitate transmitter release at theta frequency. Neuron 68 1109–1127.

    Not in our library10.1016/j.neuron.2010.11.023

  191. 191.

    Mesic I. Madry C. Geider K. Bernhard M. Betz H. Laube B. (2016 ). The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors. Neuropharmacology 105 133–141.

    Not in our library10.1016/j.neuropharm.2016.01.014

  192. 192.

    Micu I. Jiang Q. Coderre E. Ridsdale A. Zhang L. Woulfe J. (2006 ). NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439 988–992.

    Not in our library10.1038/nature04474

  193. 193.

    Mishizen-Eberz A. J. Rissman R. A. Carter T. L. Ikonomovic M. D. Wolfe B. B. Armstrong D. M. (2004 ). Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology. Neurobiol. Dis. 15 80–92.

    Not in our library10.1016/j.nbd.2003.09.016

  194. 194.

    Misra C. Brickley S. G. Farrant M. Cull-Candy S. G. (2000 ). Identification of subunits contributing to synaptic and extrasynaptic NMDA receptors in Golgi cells of the rat cerebellum. J. Physiol. 524 147–162.

    Not in our library10.1111/j.1469-7793.2000.00147.x

  195. 195.

    Molnar E. Va Radi A. McIlhinney R. A. J. Ashcroft S. J. H. (1995 ). Identification of functional ionotropic glutamate receptor proteins in pancreatic β-cells and in islets of langerhans. FEBS Lett. 371 253–257.

    Not in our library10.1016/0014-5793(95)00890-l

  196. 196.

    Momiyama A. Feldmeyer D. Cull-Candy S. G. (1996 ). Identification of a native low-conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones. J. Physiol. 494 479–492.

    Not in our library10.1113/jphysiol.1996.sp021507

  197. 197.
    A Metabotropic-Like Flux-Independent NMDA Receptor Regulates Ca2+ Exit from Endoplasmic Reticulum and Mitochondrial Membrane Potential in Cultured Astrocytes. · 2015
    Not checked
  198. 198.

    Monyer H. Burnashev N. Laurie D. J. Sakmann B. Seeburg P. H. (1994 ). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12 529–540.

    Not in our library10.1016/0896-6273(94)90210-0

  199. 199.

    Morimoto B. H. (2018 ). Therapeutic peptides for CNS indications: progress and challenges. Bioorgan Med. Chem. 26 2859–2862.

    Not in our library10.1016/j.bmc.2017.09.011

  200. 200.
    Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease · 2018
    No notice
  201. 201.

    Mota S. I. Ferreira I. L. Pereira C. Oliveira C. R. Rego A. C. (2012 ). Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures. Curr. Alzheimer Res. 9 844–856.

    Not in our library10.2174/156720512802455322

  202. 202.

    Mota S. I. Ferreira I. L. Rego A. C. (2014 ). Dysfunctional synapse in Alzheimer’s disease – A focus on NMDA receptors. Neuropharmacology 76 16–26.

    Not in our library10.1016/j.neuropharm.2013.08.013

  203. 203.

    Muller T. Albrecht D. Gebhardt C. (2009 ). Both NR2A and NR2B subunits of the NMDA receptor are critical for long-term potentiation and long-term depression in the lateral amygdala of horizontal slices of adult mice. Learn Mem. 16 395–405.

    Not in our library10.1101/lm.1398709

  204. 204.

    Murugan M. Sivakumar V. Lu J. Ling E. A. Kaur C. (2011 ). Expression of N-methyl D-aspartate receptor subunits in amoeboid microglia mediates production of nitric oxide via NF-κB signaling pathway and oligodendrocyte cell death in hypoxic postnatal rats. Glia 59 521–539.

    Not in our library10.1002/glia.21121

  205. 205.

    Nabavi S. Kessels H. W. Alfonso S. Aow J. Fox R. Malinow R. (2013 ). Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc. Natl. Acad. Sci. U.S.A. 110 4027–4032.

    Not in our library10.1073/pnas.1219454110

  206. 206.

    Nagele R. G. Andrea M. R. D. Anderson W. J. Wang H. Y. (2002 ). Intracellular accumulation of β-amyloid1–42 in neurons is facilitated by the α7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110 199–211.

    Not in our library10.1016/s0306-4522(01)00460-2

  207. 207.

    Nagy J. (2004 ). The NR2B subtype of NMDA receptor: a potential target for the treatment of alcohol dependence. Curr. Drug Targets CNS Neurol. Disord. 3 169–179.

    Not in our library10.2174/1568007043337409

  208. 208.

    Nakanishi N. Tu S. Shin Y. Cui J. Kurokawa T. Zhang D. (2009 ). Neuroprotection by the NR3A subunit of the NMDA receptor. J. Neurosci. 29 5260–5265.

    Not in our library10.1523/jneurosci.1067-09.2009

  209. 209.

    Nakazawa T. Komai S. Tezuka T. Hisatsune C. Umemori H. Semba K. (2001 ). Characterization of Fyn-mediated tyrosine phosphorylation sites on GluRε2 (NR2B) subunit of the N-Methyl-D-aspartate receptor. J. Biol. Chem. 276 693–699.

    Not in our library10.1074/jbc.m008085200

  210. 210.

    Newpher T. M. Ehlers M. D. (2008 ). Glutamate receptor dynamics in dendritic microdomains. Neuron 58 472–497.

    Not in our library10.1016/j.neuron.2008.04.030

  211. 211.

    Nilsson A. Duan J. Mo-Boquist L. L. Benedikz E. Sundström E. (2007 ). Characterisation of the human NMDA receptor subunit NR3A glycine binding site. Neuropharmacology 52 1151–1159.

    Not in our library10.1016/j.neuropharm.2006.12.002

  212. 212.

    Nishi M. Hinds H. Lu H. Kawata M. Hayashi Y. (2001 ). Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner. J. Neurosci. 21 RC185–RC185.

    Not in our library10.1523/jneurosci.21-23-j0003.2001

  213. 213.

    Nowak L. Bregestovski P. Ascher P. Herbet A. Prochiantz A. (1984 ). Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307 462–465.

    Not in our library10.1038/307462a0

  214. 214.

    Nyitrai G. Kékesi K. A. Juhász G. (2006 ). Extracellular level of GABA and Glu: in vivo microdialysis-HPLC measurements. Curr. Top. Med. Chem. 6 935–940.

    Not in our library10.2174/156802606777323674

  215. 215.

    Pachernegg S. Strutz-Seebohm N. Hollmann M. (2012 ). GluN3 subunit-containing NMDA receptors: not just one-trick ponies. Trends Neurosci. 35 240–249.

    Not in our library10.1016/j.tins.2011.11.010

  216. 216.
    Amyloid‐Beta Interaction with Mitochondria · 2011
    No notice
  217. 217.

    Palop J. J. Chin J. Roberson E. D. Wang J. Thwin M. T. Bien-Ly N. (2007 ). Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55 697–711.

    Not in our library10.1016/j.neuron.2007.07.025

  218. 218.

    Palop J. J. Mucke L. (2010 ). Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat. Neurosci. 13 812–818.

    Not in our library10.1038/nn.2583

  219. 219.

    Palygin O. Lalo U. Pankratov Y. (2011 ). Distinct pharmacological and functional properties of NMDA receptors in mouse cortical astrocytes. Br. J. Pharmacol. 163 1755–1766.

    Not in our library10.1111/j.1476-5381.2011.01374.x

  220. 220.

    Paoletti P. (2011 ). Molecular basis of NMDA receptor functional diversity. Eur. J. Neurosci. 33 1351–1365.

    Not in our library10.1111/j.1460-9568.2011.07628.x

  221. 221.

    Paoletti P. Ascher P. Neyton J. (1997 ). High-affinity zinc inhibition of NMDA NR1–NR2A receptors. J. Neurosci. 17 5711–5725.

    Not in our library10.1523/jneurosci.17-15-05711.1997

  222. 222.

    Paoletti P. Bellone C. Zhou Q. (2013 ). NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14 383–400.

    Not in our library10.1038/nrn3504

  223. 223.

    Papouin T. Ladépêche L. Ruel J. Sacchi S. Labasque M. Hanini M. (2012 ). Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150 633–646.

    Not in our library10.1016/j.cell.2012.06.029

  224. 224.

    Parameshwaran K. Dhanasekaran M. Suppiramaniam V. (2008 ). Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp. Neurol. 210 7–13.

    Not in our library10.1016/j.expneurol.2007.10.008

  225. 225.

    Park H. Popescu A. Poo M. (2014 ). Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP. Neuron 84 1009–1022.

    Not in our library10.1016/j.neuron.2014.10.045

  226. 226.

    Parsons C. G. Stöffler A. Danysz W. (2007 ). Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system – Too little activation is bad, too much is even worse. Neuropharmacology 53 699–723.

    Not in our library10.1016/j.neuropharm.2007.07.013

  227. 227.

    Patel L. Grossberg G. (2011 ). Combination therapy for Alzheimer’s disease. Drugs Aging 28 539–546.

    Not in our library10.2165/11591860-000000000-00000

  228. 228.

    Paterlini M. Valerio A. Baruzzi F. Memo M. Spano P. (1998 ). Opposing regulation of tau protein levels by ionotropic and metabotropic glutamate receptors in human NT2 neurons. Neurosci. Lett. 243 77–80.

    Not in our library10.1016/s0304-3940(98)00087-1

  229. 229.

    Pérez-Otaño I. Larsen R. S. Wesseling J. F. (2016 ). Emerging roles of GluN3-containing NMDA receptors in the CNS. Nat. Rev. Neurosci. 17 623–635.

    Not in our library10.1038/nrn.2016.92

  230. 230.

    Perez-Otano I. Schulteis C. T. Contractor A. Lipton S. A. Trimmer J. S. Sucher N. J. (2001 ). Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J. Neurosci. 21 1228–1237.

    Not in our library10.1523/jneurosci.21-04-01228.2001

  231. 231.

    Perszyk R. E. DiRaddo J. O. Strong K. L. Low C. M. Ogden K. K. Khatri A. (2016 ). GluN2D-containing N-methyl-D-Aspartate receptors mediate synaptic transmission in hippocampal interneurons and regulate interneuron activity. Mol. Pharmacol. 90 689–702.

    Not in our library10.1124/mol.116.105130

  232. 232.

    Petralia R. S. Al-Hallaq R. A. Wenthold R. J. (2009 ). “Trafficking and targeting of NMDA receptors,” in Biology of the NMDA Receptor, Chap. 8 ed. VanDongen A. M. (Boca Raton, FL: CRC Press/Taylor & Francis).

    Not in our library

  233. 233.

    Pierson T. M. Yuan H. Marsh E. D. Fuentes-Fajardo K. Adams D. R. Markello T. (2014 ). GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann. Clin. Trans. Neurol. 1 190–198.

    Not in our library10.1002/acn3.39

  234. 234.

    Prybylowski K. Fu Z. Losi G. Hawkins L. M. Luo J. Chang K. (2002 ). Relationship between availability of NMDA receptor subunits and their expression at the synapse. J. Neurosci. 22 8902–8910.

    Not in our library10.1523/jneurosci.22-20-08902.2002

  235. 235.

    Puzzo D. Privitera L. Leznik E. Fa M. Staniszewski A. Palmeri A. (2008 ). Picomolar amyloid- positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 28 14537–14545.

    Not in our library10.1523/jneurosci.2692-08.2008

  236. 236.

    Raveendran R. Devi Suma Priya S. Mayadevi M. Steephan M. Santhoshkumar T. R. (2009 ). Phosphorylation status of the NR2B subunit of NMDA receptor regulates its interaction with calcium/calmodulin-dependent protein kinase II. J. Neurochem. 110 92–105.

    Not in our library10.1111/j.1471-4159.2009.06108.x

  237. 237.

    Regan M. C. Grant T. McDaniel M. J. Karakas E. Zhang J. Traynelis S. F. (2018 ). Structural mechanism of functional modulation by gene splicing in NMDA receptors. Neuron 98 521.e3–529.e3.

    Not in our library10.1016/j.neuron.2018.03.034

  238. 238.

    Regan M. C. Romero-Hernandez A. Furukawa H. (2015 ). A structural biology perspective on NMDA receptor pharmacology and function. Curr. Opin. Struct. Biol. 33 68–75.

    Not in our library10.1016/j.sbi.2015.07.012

  239. 239.

    Reisberg B. Doody R. Stöffler A. Schmitt F. Ferris S. Möbius H. J. (2003 ). Memantine in moderate-to-severe Alzheimer’s disease. New. Engl. J. Med. 348 1333–1341.

    Not in our library10.1056/nejmoa013128

  240. 240.

    Reynolds C. H. Garwood C. J. Wray S. Price C. Kellie S. Perera T. (2008 ). Phosphorylation regulates tau interactions with src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cγ1, Grb2, and Src family kinases. J. Biol. Chem. 283 18177–18186.

    Not in our library10.1074/jbc.m709715200

  241. 241.

    Rice L. Bisdas S. (2017 ). The diagnostic value of FDG and amyloid PET in Alzheimer’s disease-a systematic review. Eur. J. Radiol. 94 16–24.

    Not in our library10.1016/j.ejrad.2017.07.014

  242. 242.

    Roberson E. D. Scearce-Levie K. Palop J. J. Yan F. Cheng I. H. Wu T. (2007 ). Reducing endogenous tau ameliorates amyloid-induced deficits in an Alzheimer’s disease mouse model. Science 316 750–754.

    Not in our library10.1126/science.1141736

  243. 243.

    Roberts A. C. Díez-García J. Rodriguiz R. M. López I. P. Luján R. Martínez-Turrillas R. (2009 ). Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63 342–356.

    Not in our library10.1016/j.neuron.2009.06.016

  244. 244.

    Rogaeva E. Meng Y. Lee J. H. Gu Y. Kawarai T. Zou F. (2007 ). The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat. Genet. 39 168–177.

    Not in our library10.1038/ng1943

  245. 245.

    Rong Y. Lu X. Bernard A. Khrestchatisky M. Baudry M. (2001 ). Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95. J. Neurochem. 79 382–390.

    Not in our library10.1046/j.1471-4159.2001.00565.x

  246. 246.

    Rönicke R. Mikhaylova M. Rönicke S. Meinhardt J. Schröder U. H. Fändrich M. (2011 ). Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiol. Aging 32 2219–2228.

    Not in our library10.1016/j.neurobiolaging.2010.01.011

  247. 247.

    Roselli F. Tirard M. Lu J. Hutzler P. Lamberti P. Livrea P. (2005 ). Soluble β-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J. Neurosci. 25 11061–11070.

    Not in our library10.1523/jneurosci.3034-05.2005

  248. 248.

    Rossi B. Ogden D. Llano I. Tan Y. P. Marty A. Collin T. (2012 ). Current and calcium responses to local activation of axonal NMDA receptors in developing cerebellar molecular layer interneurons. PLoS One 7:e39983.

    Not in our library10.1371/journal.pone.0039983

  249. 249.

    Rothman S. M. Olney J. W. (1986 ). Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19 105–111.

    Not in our library10.1002/ana.410190202

  250. 250.

    Ruthirakuhan M. Herrmann N. Suridjan I. Abraham E. H. Farber I. Lanctot K. L. (2016 ). Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’s disease. Expert Opin. Pharmacother. 17 2417–2429.

    Not in our library10.1080/14656566.2016.1258060

  251. 251.

    Salomone S. Caraci F. Leggio G. M. Fedotova J. Drago F. (2012 ). New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs. Br. J. Clin. Pharmacol. 73 504–517.

    Not in our library10.1111/j.1365-2125.2011.04134.x

  252. 252.

    Salter M. G. Fern R. (2005 ). NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438 1167–1171.

    Not in our library10.1038/nature04301

  253. 253.

    Salter M. W. Kalia L. V. (2004 ). Src kinases: a hub for NMDA receptor regulation. Nat. Rev. Neurosci. 5 317–328.

    Not in our library10.1038/nrn1368

  254. 254.

    Sanders E. M. Nyarko-Odoom A. O. Zhao K. Nguyen M. Liao H. H. Keith M. (2018 ). Separate functional properties of NMDARs regulate distinct aspects of spatial cognition. Learn Mem. 25 264–272.

    Not in our library10.1101/lm.047290.118

  255. 255.

    Sanderson J. L. Gorski J. A. Dell’Acqua M. L. (2016 ). NMDA receptor-dependent LTD requires transient synaptic incorporation of Ca(2)(+)-permeable AMPARs mediated by AKAP150-anchored PKA and calcineurin. Neuron 89 1000–1015.

    Not in our library10.1016/j.neuron.2016.01.043

  256. 256.

    Sans N. Petralia R. S. Wang Y. Blahos J. Hell J. W. Wenthold R. J. (2000 ). A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20 1260–1271.

    Not in our library10.1523/jneurosci.20-03-01260.2000

  257. 257.

    Sanz-Clemente A. Nicoll R. A. Roche K. W. (2012 ). Diversity in NMDA receptor composition. Neuroscientist 19 62–75.

    Not in our library10.1177/1073858411435129

  258. 258.

    Sattler R. Xiong Z. Lu W. MacDonald J. F. Tymianski M. (2000 ). Distinct roles of synaptic and extrasynaptic NMDA receptors in excitotoxicity. J. Neurosci. 20 22–33.

    Not in our library10.1523/jneurosci.20-01-00022.2000

  259. 259.

    Shankar G. M. Bloodgood B. L. Townsend M. Walsh D. M. Selkoe D. J. Sabatini B. L. (2007 ). Natural oligomers of the Alzheimer amyloid- protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27 2866–2875.

    Not in our library10.1523/jneurosci.4970-06.2007

  260. 260.

    Sheng M. Lee S. H. (2000 ). Growth of the NMDA receptor industrial complex. Nat. Neurosci. 3 633–635.

    Not in our library10.1038/76576

  261. 261.

    Shi X. Sun K. Hu R. Liu X. Hu Q. Sun X. (2016 ). Blocking the Interaction between EphB2 and ADDLs by a small peptide rescues impaired synaptic plasticity and memory deficits in a mouse model of Alzheimer’s disease. J. Neurosci. 36 11959–11973.

    Not in our library10.1523/jneurosci.1327-16.2016

  262. 262.

    Sindou P. Couratier P. Barthe D. Hugon J. (1992 ). A dose-dependent increase of Tau immunostaining is produced by glutamate toxicity in primary neuronal cultures. Brain Res. 572 242.

    Not in our library10.1016/0006-8993(92)90476-p

  263. 263.

    Sindou P. Lesort M. Couratier P. Yardin C. Esclaire F. Hugon J. (1994 ). Glutamate increases tau phosphorylation in primary neuronal cultures from fetal rat cerebral cortex. Brain Res. 646 124.

    Not in our library10.1016/0006-8993(94)90064-7

  264. 264.

    Sinor J. D. Du S. Venneti S. Blitzblau R. C. Leszkiewicz D. N. Rosenberg P. A. (2000 ). NMDA and glutamate evoke excitotoxicity at distinct cellular locations in rat cortical neurons in vitro. J. Neurosci. 20 8831–8837.

    Not in our library10.1523/jneurosci.20-23-08831.2000

  265. 265.

    Smothers C. T. Woodward J. J. (2003 ). Effect of the NR3 subunit on ethanol inhibition of recombinant NMDA receptors. Brain Res. 987 117–121.

    Not in our library10.1016/s0006-8993(03)03315-8

  266. 266.

    Snyder E. M. Nong Y. Almeida C. G. Paul S. Moran T. Choi E. Y. (2005 ). Regulation of NMDA receptor trafficking by amyloid-β. Nat. Neurosci. 8 1051–1058.

    Not in our library10.1038/nn1503

  267. 267.

    Sofroniew M. V. (2009 ). Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32 638–647.

    Not in our library10.1016/j.tins.2009.08.002

  268. 268.

    Song X. Jensen M. Ø. Jogini V. Stein R. A. Lee C. Mchaourab H. S. (2018 ). Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature 556 515–519.

    Not in our library10.1038/s41586-018-0039-9

  269. 269.

    Sproul A. Steele S. L. Thai T. L. Yu S. Klein J. D. Sands J. M. (2011 ). N-methyl-D-aspartate receptor subunit NR3a expression and function in principal cells of the collecting duct. Am. J. Physiol. Renal. Physiol. 301 F44–F54.

    Not in our library10.1152/ajprenal.00666.2010

  270. 270.

    Stein I. S. Gray J. A. Zito K. (2015 ). Non-ionotropic NMDA receptor signaling drives activity-induced dendritic spine shrinkage. J. Neurosci. 35 12303–12308.

    Not in our library10.1523/jneurosci.4289-14.2015

  271. 271.

    Stroebel D. Carvalho S. Grand T. Zhu S. Paoletti P. (2014 ). Controlling NMDA receptor subunit composition using ectopic retention signals. J. Neurosci. 34 16630–16636.

    Not in our library10.1523/jneurosci.2736-14.2014

  272. 272.

    Sucher N. J. Akbarian S. Chi C. L. Leclerc C. L. Awobuluyi M. Deitcher D. L. (1995 ). Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J. Neurosci. 15 6509–6520.

    Not in our library10.1523/jneurosci.15-10-06509.1995

  273. 273.

    Suga K. Saito A. Akagawa K. (2015 ). ER stress response in NG108-15 cells involves upregulation of syntaxin 5 expression and reduced amyloid β peptide secretion. Exp. Cell Res. 332 11–23.

    Not in our library10.1016/j.yexcr.2015.01.001

  274. 274.

    Sumi M. Kiuchi K. Ishikawa T. Ishii A. Hagiwara M. Nagatsu T. (1991 ). The newly synthesized selective Ca2+/calmodulin dependent protein kinase II inhibitor KN-93 reduces dopamine contents in PC12h cells. Biochem. Biophys. Res. Commun. 181 968–975.

    Not in our library10.1016/0006-291x(91)92031-e

  275. 275.

    Sun W. Hansen K. B. Jahr C. E. (2017 ). Allosteric interactions between NMDA receptor subunits shape the developmental shift in channel properties. Neuron 94 58.e3–64.e3.

    Not in our library10.1016/j.neuron.2017.03.018

  276. 276.

    Sun X. Tuo Q. Liuyang Z. Xie A. Feng X. Yan X. (2016 ). Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronal death through suppressing survival signaling ERK phosphorylation. Cell Death Dis. 7:e2449.

    Not in our library10.1038/cddis.2016.329

  277. 277.

    Sundström E. Whittemore S. Mo L. Seiger Å. (1997 ). Analysis of NMDA receptors in the human spinal cord. Exp. Neurol. 148 407–413.

    Not in our library10.1006/exnr.1997.6691

  278. 278.

    Swanger S. A. Vance K. M. Acker T. M. Zimmerman S. S. DiRaddo J. O. Myers S. J. (2017 ). A novel negative allosteric modulator selective for GluN2C/2D-containing NMDA receptors inhibits synaptic transmission in hippocampal interneurons. ACS Chem. Neurosci. 9 306–319.

    Not in our library10.1021/acschemneuro.7b00329

  279. 279.

    Szasz B. K. Mike A. Karoly R. Gerevich Z. Illes P. Vizi E. S. (2007 ). Direct inhibitory effect of fluoxetine on N-Methyl-D-Aspartate receptors in the central nervous system. Biol. Psychiatry 62 1303–1309.

    Not in our library10.1016/j.biopsych.2007.04.014

  280. 280.

    Sze C. Bi H. Kleinschmidt-DeMasters B. K. Filley C. M. Martin L. J. (2001 ). N-Methyl- D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer’s disease. J. Neurol. Sci. 182 151–159.

    Not in our library10.1016/s0022-510x(00)00467-6

  281. 281.

    Takai H. Katayama K. Uetsuka K. Nakayama H. Doi K. (2003 ). Distribution of N-methyl-D-aspartate receptors (NMDARs) in the developing rat brain. Exp. Mol. Pathol. 75 89–94.

    Not in our library10.1016/s0014-4800(03)00030-3

  282. 282.
    NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression. · 2013
    Not checked
  283. 283.

    Tayeb H. O. Yang H. D. Price B. H. Tarazi F. I. (2012 ). Pharmacotherapies for Alzheimer’s disease: beyond cholinesterase inhibitors. Pharmacol. Therapeut. 134 8–25.

    Not in our library10.1016/j.pharmthera.2011.12.002

  284. 284.

    Texidó L. Martín-Satué M. Alberdi E. Solsona C. Matute C. (2011 ). Amyloid β peptide oligomers directly activate NMDA receptors. Cell Calcium 49 184–190.

    Not in our library10.1016/j.ceca.2011.02.001

  285. 285.
    PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-d-aspartate receptor subunit NR2A · 1999
    Not checked
  286. 286.

    Thiels E. Xie X. Yeckel M. F. Barrionuevo G. Berger T. W. (1996 ). NMDA receptor-dependent LTD in different subfields of hippocampus in vivo and in vitro. Hippocampus 6 43–51.

    Not in our library10.1002/(sici)1098-1063(1996)6:1<43::aid-hipo8>3.0.co;2-8

  287. 287.

    Thomas C. G. Miller A. J. Westbrook G. L. (2006 ). Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons. J. Neurophysiol. 95 1727–1734.

    Not in our library10.1152/jn.00771.2005

  288. 288.

    Thomas S. M. Brugge J. S. (1997 ). Cellular functions regulated by Src family kinases. Annu. Rev. Cell Dev. Biol. 13 513–609.

    Not in our library10.1146/annurev.cellbio.13.1.513

  289. 289.
    Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease · 2009
    No notice
  290. 290.

    Tovar K. R. Westbrook G. L. (2017 ). Modulating synaptic NMDA receptors. Neuropharmacology 112 29–33.

    Not in our library10.1016/j.neuropharm.2016.08.023

  291. 291.

    Townsend M. Yoshii A. Mishina M. Constantine-Paton M. (2003 ). Developmental loss of miniature N-methyl-D-aspartate receptor currents in NR2A knockout mice. Proc. Natl. Acad. Sci. U.S.A. 100 1340–1345.

    Not in our library10.1073/pnas.0335786100

  292. 292.

    Traynelis S. F. Wollmuth L. P. McBain C. J. Menniti F. S. Vance K. M. Ogden K. K. (2010 ). Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62 405–496.

    Not in our library10.1124/pr.109.002451

  293. 293.

    Tymianski M. Charlton M. P. Carlen P. L. Tator C. H. (1993 ). Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J. Neurosci. 13 2085–2104.

    Not in our library10.1523/jneurosci.13-05-02085.1993

  294. 294.

    Ułas J. Cotman C. W. (1997 ). Decreased expression of N-methyl-D-aspartate receptor 1 messenger RNA in select regions of Alzheimer brain. Neuroscience 79 973–982.

    Not in our library10.1016/s0306-4522(97)00023-7

  295. 295.

    Ullian E. M. Barkis W. B. Chen S. Diamond J. S. Barres B. A. (2004 ). Invulnerability of retinal ganglion cells to NMDA excitotoxicity. Mol. Cell. Neurosci. 26 544–557.

    Not in our library10.1016/j.mcn.2004.05.002

  296. 296.

    Um J. W. Kaufman A. C. Kostylev M. Heiss J. K. Stagi M. Takahashi H. (2013 ). Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79 887–902.

    Not in our library10.1016/j.neuron.2013.06.036

  297. 297.

    Um J. W. Nygaard H. B. Heiss J. K. Kostylev M. A. Stagi M. Vortmeyer A. (2012 ). Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15 1227–1235.

    Not in our library10.1038/nn.3178

  298. 298.

    Usardi A. Pooler A. M. Seereeram A. Reynolds C. H. Derkinderen P. Anderton B. (2011 ). Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. FEBS J. 278 2927–2937.

    Not in our library10.1111/j.1742-4658.2011.08218.x

  299. 299.

    Verges D. K. Restivo J. L. Goebel W. D. Holtzman D. M. Cirrito J. R. (2011 ). Opposing synaptic regulation of amyloid-beta metabolism by NMDA receptors in vivo. J. Neurosci. 31 11328–11337.

    Not in our library10.1523/jneurosci.0607-11.2011

  300. 300.

    Vicini S. Wang J. F. Li J. H. Zhu W. J. Wang Y. H. Luo J. H. (1998 ). Functional and pharmacological differences between recombinant N-Methyl-D-aspartate receptors. J. Neurophysiol. 79 555–566.

    Not in our library10.1152/jn.1998.79.2.555

  301. 301.

    Villmann C. Becker C. (2007 ). On the hypes and falls in neuroprotection: targeting the NMDA receptor. Neuroscientist 13 594–615.

    Not in our library10.1177/1073858406296259

  302. 302.

    Vizi E. S. (2000 ). Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the central nervous system. Pharmacol. Rev. 52 63–89.

    Not in our library

  303. 303.

    Vizi E. S. Kisfali M. Lõrincz T. (2013 ). Role of nonsynaptic GluN2B-containing NMDA receptors in excitotoxicity: evidence that fluoxetine selectively inhibits these receptors and may have neuroprotective effects. Brain Res. Bull. 93 32–38.

    Not in our library10.1016/j.brainresbull.2012.10.005

  304. 304.
    Long-term potentiation and the role of N -methyl- d -aspartate receptors · 2015
    No notice
  305. 305.

    Wake H. Lee P. R. Fields R. D. (2011 ). Control of local protein synthesis and initial events in myelination by action potentials. Science 333 1647–1651.

    Not in our library10.1126/science.1206998

  306. 306.

    Walsh D. M. Klyubin I. Fadeeva J. V. Cullen W. K. Anwyl R. Wolfe M. S. (2002 ). Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416 535–539.

    Not in our library10.1038/416535a

  307. 307.

    Walsh D. M. Tseng B. P. Rydel R. E. Podlisny M. B. Selkoe D. J. (2000 ). The oligomerization of amyloid β-protein begins intracellularly in cells derived from human brain†. Biochemistry-US 39 10831–10839.

    Not in our library10.1021/bi001048s

  308. 308.

    Wang C. Pralong W. Schulz M. Rougon G. Aubry J. Pagliusi S. (1996 ). Functional N-Methyl-D-aspartate receptors in O-2A glial precursor cells: a critical role in regulating polysialic acid-neural cell adhesion molecule expression and cell migration. J. Cell Biol. 135 1565–1581.

    Not in our library10.1083/jcb.135.6.1565

  309. 309.

    Wang H. Y. Lee D. H. D’Andrea M. R. Peterson P. A. Shank R. P. Reitz A. B. (2000 ). beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. implications for Alzheimer’s disease pathology. J. Biol. Chem. 275 5626–5632.

    Not in our library10.1074/jbc.275.8.5626

  310. 310.

    Wang R. Reddy P. H. (2017 ). Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimer’s Dis. 57 1041–1048.

    Not in our library10.3233/jad-160763

  311. 311.

    Wang Z. Zhao J. Li S. (2013 ). Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-β. Neurosci. Bull. 29 752–760.

    Not in our library10.1007/s12264-013-1383-2

  312. 312.

    Wee K. S. L. Zhang Y. Khanna S. Low C. (2008 ). Immunolocalization of NMDA receptor subunit NR3B in selected structures in the rat forebrain, cerebellum, and lumbar spinal cord. J. Comp. Neurol. 509 118–135.

    Not in our library10.1002/cne.21747

  313. 313.

    Wenk G. L. (2006 ). Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J. Clin. Psychiatry 67 (Suppl. 3), 3–7; quiz 23.

    Not in our library

  314. 314.

    Whitesell J. D. Buckley A. R. Knox J. E. Kuan L. Graddis N. Pelos A. (2018 ). Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer’s disease. J. Comp. Neurol. [Epub ahead of print].

    Not in our library10.1002/cne.24555

  315. 315.

    Wilkinson D. Fox N. C. Barkhof F. Phul R. Lemming O. Scheltens P. (2012 ). Memantine and brain atrophy in Alzheimer’s disease: a 1-Year randomized controlled trial. J. Alzheimers Dis. 29 459–469.

    Not in our library10.3233/jad-2011-111616

  316. 316.

    Williams K. (1993 ). Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 44:851.

    Not in our library

  317. 317.

    Wong J. M. Gray J. A. (2018 ). Long-term depression is independent of GluN2 subunit composition. J. Neurosci. 38 4462–4470.

    Not in our library10.1523/jneurosci.0394-18.2018

  318. 318.

    Wu H. Tzeng N. Qian L. Wei S. Hu X. Chen S. (2009 ). Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology 34 2344–2357.

    Not in our library10.1038/npp.2009.64

  319. 319.

    Wu H. Y. Hudry E. Hashimoto T. Kuchibhotla K. Rozkalne A. Fan Z. (2010 ). Amyloid induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J. Neurosci. 30 2636–2649.

    Not in our library10.1523/jneurosci.4456-09.2010

  320. 320.

    Yang J. Sophie E. L. C. Woodhall G. L. Roland S. G. J. (2008 ). Mobility of NMDA autoreceptors but not postsynaptic receptors at glutamate synapses in the rat entorhinal cortex. J. Physiol. 586 4905–4924.

    Not in our library10.1113/jphysiol.2008.157974

  321. 321.

    Yang J. Woodhall G. L. Jones R. S. G. (2006 ). Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDA receptors is increased in the entorhinal cortex of chronically epileptic rats. J. Neurosci. 26 406–410.

    Not in our library10.1523/jneurosci.4413-05.2006

  322. 322.

    Yao Y. (2006 ). Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J. Neurosci. 26 4559–4566.

    Not in our library10.1523/jneurosci.0560-06.2006

  323. 323.

    Yao Y. Harrison C. B. Freddolino P. L. Schulten K. Mayer M. L. (2008 ). Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors. EMBO J. 27 2158–2170.

    Not in our library10.1038/emboj.2008.140

  324. 324.

    Yashiro K. Philpot B. D. (2008 ). Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55 1081–1094.

    Not in our library10.1016/j.neuropharm.2008.07.046

  325. 325.

    Yi F. Mou T. Dorsett K. N. Volkmann R. A. Menniti F. S. Sprang S. R. (2016 ). Structural basis for negative allosteric modulation of GluN2A-containing NMDA receptors. Neuron 91 1316–1329.

    Not in our library10.1016/j.neuron.2016.08.014

  326. 326.

    Yu A. Lau A. Y. (2018 ). Glutamate and glycine binding to the NMDA receptor. Structure 26 1035.e2–1043.e2.

    Not in our library10.1016/j.str.2018.05.004

  327. 327.

    Yux L. X. Foster T. P. Sarver R. W. Moseley W. M. (1996 ). Preparation, characterization, and in vivo evaluation of an oil suspension of a bovine growth hormone releasing factor analog. J. Pharm. Sci.-U.S. 85 396–401.

    Not in our library10.1021/js950110h

  328. 328.

    Zempel H. Thies E. Mandelkow E. Mandelkow E. M. (2010 ). Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous tau into dendrites, tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30 11938–11950.

    Not in our library10.1523/jneurosci.2357-10.2010

  329. 329.

    Zhang J. Diamond J. S. (2006 ). Distinct perisynaptic and synaptic localization of NMDA and AMPA receptors on ganglion cells in rat retina. J. Comp. Neurol. 498 810–820.

    Not in our library10.1002/cne.21089

  330. 330.

    Zhou X. Ding Q. Chen Z. Yun H. Wang H. (2013a ). Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic n-methyl-D-aspartate receptor function and neuronal excitotoxicity. J. Biol. Chem. 288 24151–24159.

    Not in our library10.1074/jbc.m113.482000

  331. 331.

    Zhou X. Hollern D. Liao J. Andrechek E. Wang H. (2013b ). NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors. Cell Death Dis. 4 e560–e560.

    Not in our library10.1038/cddis.2013.82

  332. 332.

    Zhu J. J. Qin Y. Zhao M. Van Aelst L. Malinow R. (2002 ). Ras and rap Control AMPA receptor trafficking during synaptic plasticity. Cell 110 443–455.

    Not in our library10.1016/s0092-8674(02)00897-8

  333. 333.

    Zhu S. Paoletti P. (2015 ). Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr. Opin. Pharmacol. 20 14–23.

    Not in our library10.1016/j.coph.2014.10.009

  334. 334.

    Zong N. Li F. Deng Y. Shi J. Jin F. Gong Q. (2016 ). Icariin, a major constituent from Epimedium brevicornum, attenuates ibotenic acid-induced excitotoxicity in rat hippocampus. Behav. Brain Res. 313 111–119.

    Not in our library10.1016/j.bbr.2016.06.055

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