Developmental origins of brain disorders: roles for dopamine

1Brain development requires a complex interplay of genetic and environmental factors. Disruption of these elements can affect neuronal structure, function, or connectivity and can alter developmental trajectory. In turn, this can lead to long-lasting, even permanent, effects and contribute to brain disorders later in life. Neurodevelopmental alterations in the frontal/prefrontal cortex and striatum, which are both heavily involved in cognition, memory, emotion, and learning, are likely involved in the etiology of neuropsychiatric disorders like autism, substance use disorders, and schizophrenia. These brain regions receive prominent dopamine (DA) innervations and express DA receptors. In fact, DA and other neurotransmitters are expressed even prior to synaptogenesis, and activation of their receptors during development alters brain structure and connectivity with enduring anatomical and behavioral effects through adulthood. However, the cellular and functional consequences of these activities are still poorly understood, and their linkages to specific diseases are often indirect and poorly elucidated.

2Here we will review evidence for the role of DA receptors in neurodevelopmental processes with an emphasis on how DA D1 and D2 receptors modulate neuronal morphology in the frontal cortex and striatum. We will then briefly discuss the relevant intracellular signaling mechanisms through which DA receptors modulate neuronal morphology, and conclude with the implications of altered DA signaling on our understanding of the etiology and pathophysiology of neuropsychiatric disorders.

3DA innervation and receptor expression are present early in development, mature during adolescence, and form stable patterns in young adulthood. This prolonged developmental timeline provides a large window of “critical periods” during which potential disruptors can induce varied effects. For example, a landmark study by showed that repeated exposure to methylphenidate (Ritalin) during the juvenile period reduces cocaine reward in adulthood, whereas adult methylphenidate exposure does not confer this protection.

4Alterations in DA innervation patterns and receptor expression have been found in several brain disorders, including psychiatric disease. A decrease in DAergic axons in deep layers of medial prefrontal cortex and decreased D1 receptor binding occurs in schizophrenic patients. In addition, increased D2 receptor binding in the striatum has been observed in patients with ADHD and depression. An understanding of the developmental timeline of the DA system and points at which the normal developmental trajectory can be altered are crucial to explore the implications of DAergic disruption.

5The frontal cortex and striatum are innervated by DA-containing axons from the mesencephalic DA nuclei by mid-to-late gestation in rodents, the predominant animal models used to study the developmental roles of DA. demonstrated that DA innervation develops in well-defined spatiotemporal gradients in the lateral ganglionic eminence (presumptive striatum) that begins by embryonic day (E) 14 and coincides with striatal neurogenesis and cell differentiation. The rat developing cortex receives DAergic fibers that pass through the striatum, with innervation occurring in a lateral (E16) to medial fashion (E19). At birth, DAergic fibers are concentrated in the developing layer VI of frontal cortex. Fiber density increases over time in the deep layers of cortex with some fibers innervating more superficial layers in discrete cortical regions as the more superficial cortical layers develop. Mature DAergic innervation patterns are established in both regions by postnatal day 60. Studies in other species suggest that these sequences of events are very well conserved evolutionarily, although the exact timings are of course quite different based on gestation length (see below).

6Dopamine receptor expression develops in concert with DAergic innervation. DA receptors are part of the G-protein coupled receptor superfamily and can be classified into two subgroups based on sequence, pharmacology, and G protein signaling: D1-like, which includes D1 and D5 receptors, and D2-like, which includes D2, D3, and D4 receptors. Even before DAergic afferents have fully occupied the striatum or cortex, the main two DA receptor subtypes (D1 and D2 receptors) are already present. Higher levels of expression for both subtypes are found in the striatum compared to frontal cortex from development to adulthood, and the D1 receptor subtype is expressed at higher levels than the D2 receptor subtype in both regions. D3, D4, and D5 receptors are consistently expressed at lower levels but still are present even during prenatal development. For example, D3 and D5 receptor mRNA is first found in the striatum at E12 and frontal cortex by E15. However, D4 receptor mRNA, which is also present in the striatum at E12 and frontal cortex by E15, has its highest expression during embryonic development. D4 receptor mRNA decreases after birth with a more significant drop in expression seen in the frontal cortex. D3 receptors are also are expressed transiently within the early postnatal somatosensory cortex during a key critical period of plasticity, although their function there remains unknown.

7Dopaminergic development continues postnatally and impacts forebrain synaptogenesis and connectivity. For example, D1 receptor pruning is specifically associated with maturation of the excitation-inhibition balance in frontal cortex during adolescence. demonstrated that D1 receptor expression steadily declines after the fourth postnatal week, which has been confirmed by others and is illustrated in Figure 1C. Cortical circuits and processing relies on connectivity and excitability of both excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons. Disruptions of excitation-inhibition balance in the frontal cortex have been reported in patients with schizophrenia, autism, major depressive disorder, and obsessive compulsive disorder, and many of these patients present with a first episode around adolescence. Risk of substance abuse disorders also increases during adolescence. Genetically mediated DA variability has been suggested to shape complex behaviors emerging in adolescence, such as impulsivity and sensation seeking. DAergic regulation of frontal cortex output to subcortical areas mediates drug seeking behavior, with D1 receptor activation enhancing cortically driven drug seeking. Moreover, cortical output neurons to the nucleus accumbens, a subcortical reward area, express higher levels of D1 receptors during adolescence in rodent models. This correlates with increased sensitivity to cocaine conditioned place preference. found this increased preference to be enhanced with microinjections of D1-like receptor agonist in the prefrontal cortex but blunted with D1-like receptor antagonist, demonstrating the importance of D1 receptor signaling in heightened adolescent sensitivity to cocaine preference. This work demonstrates how the prolonged development of the DA system allows for vulnerability into adolescence. Thus, inappropriate alterations in D1 receptor signaling during adolescent cortical maturation could play a significant role in the development of neuropsychiatric diseases.

8Phylogenetic differences in brain development exist between rodents and higher mammals. In regards to DA, monkeys and humans have more widespread cortical DA input than rodents and significantly denser DAergic innervation in motor, premotor, and supplementary motor association cortices. Human DAergic innervation occurs early in development and is strongly established by mid-gestation. The density of DAergic fibers to the prefrontal cortex in non-human primates increases during preadolescence, peaks during adolescence, and then declines. This evolution of the cortical DAergic system in primates suggests a more substantial role for DAergic innervation in development in more evolved species. The increased influence of DA in the human brain is exemplified by the increase in neuropsychiatric disease onset during adolescence, the time period when the DA system matures. The role of DA system development in neuropsychiatric disease vulnerability is an active area of research, and hopefully, the field will soon understand how to correct aberrant DA development in these vulnerable individuals.

9The striatum receives DAergic innervation from the substantia nigra pars compacta, which is known as the nigrostriatal pathway (shown in Figure 2). These DAergic afferents synapse on two distinct populations of GABAergic projection neurons, which express either D1 or D2 receptors (demonstrated in Figure 1D;;; ). These populations send projections directly to or indirectly through the globus pallidus (external globus pallidus in primates) to the substantia nigra pars reticulata and endopeduncular nucleus (internal globus pallidus in primates) to make up the direct (D1 receptor expressing neurons) and indirect (D2 receptor expressing neurons) pathways to modulate movement and goal-oriented behavior. Dysfunction within these pathways is a hallmark feature of multiple movement disorders, such as Parkinsonism and Huntingdon’s disease. Medications that target DA receptors can also modulate these pathways. For example, typical antipsychotics modulate this system by blocking D2 receptors; this action treats positive symptoms but can also lead to tardive dyskinesia, a serious side effect characterized by involuntary, repetitive movements. The importance of the nigrostriatal DAergic projections onto the direct and indirect pathway projection neurons is made evident by the devastating symptoms that result from disruption of this pathway, but other DAergic pathways can also play an important role in disease.

10The ventral tegmental area (VTA), another mesencephalic nucleus, gives rise to two additional DAergic pathways. Projections from the VTA to limbic areas, such as the nucleus accumbens, and to the frontal cortex form the mesolimbic and mesocortical pathways (shown in Figure 2), respectively. In the nucleus accumbens, patterns of D1 and D2 receptor expression are similar to the dorsal striatum (demonstrated in Figure 1D). In addition, the shell of the nucleus accumbens expresses high levels of D3 receptors. DA receptor expression is lower in the frontal cortex and found in several types of neurons. In the frontal cortex, D1 receptors appear to be the most prominent DA receptor, and both D1 and D2 receptors are found in deep layer V/VI glutamatergic projection neurons and parvalbumin-containing GABAergic interneurons. D4 and D5 receptors are expressed at low levels in frontal cortex. Importantly, these pathways and DA receptor expression patterns have great functional significance. The mesolimbic pathway is mainly associated with reward, while the mesocortical pathway is associated with cognitive function. Aberrant reward processing drives substance abuse disorders, and cognitive dysfunction exists as an often overlooked but devastating feature of many neuropsychiatric disorders. Studies of imbalanced mesolimbic and mesocortical DAergic signaling support a potential therapeutic role for DA in reward and cognitive dysfunction in neuropsychiatric disease. Thus, DA can influence multiple aspects of human behavior both directly through striatal projections and indirectly through alterations in reward and cognition (for description of the trajectories of growing DA axons and signals contributing to topography, see ).

11DA is one of the earliest neurotransmitters expressed in the developing brain and plays a significant role in the development of neuronal cytoarchitecture. The presence of DAergic projections to the developing cortex and striatum, as well as DA receptors on precursor cells, places DA in an ideal position to modulate neuronal development, including cell proliferation, migration, and differentiation all of which can lead to altered connectivity and dysfunctional synapses. In fact, genetic and pharmacologic models of disrupted DA signaling display changes in cortical and striatal circuitry. Environmental, social, and inflammatory challenges during sensitive periods of forebrain development also produce neuro(mal)adaptions in these regions and phenocopy some aspects of brain disorders. For example, models of prenatal infection, stress, and exposure to drugs of abuse show long-lasting changes in DA receptor expression and function and have been associated with increased risk for psychiatric disorders. Taken together, these data have led our group and others to hypothesize that DAergic modulation of developmental processes produces long lasting alterations that contribute to cortical and striatal dysfunction in neuropsychiatric disorders.

12The earliest observed developmental effects of altered DA signaling are changes in neuroprogenitor proliferation. Selective D1-like receptor agonists can decrease incorporation of the cell cycle marker bromodeoxyuridine (BrdU) in the developing medial frontal cortex and lateral ganglionic eminence, a basal forebrain progenitor pool that is the source for most striatal neurons (illustrated in Figure 1A). Decreased BrdU incorporation is indicative of less neuronal progenitors undergoing division. Both D1-like and D2-like receptors contribute to neurogenesis but with opposite effects; blockade of D1-like receptors and activation of D2-like receptors increase the number of neuronal progenitors undergoing cell division. Administration of the DA precursor L-DOPA during early gestation decreases cell proliferation, suggesting that D1 receptor mediated effects may dominate in vivo. Although these studies did not mechanistically investigate how D1 and D2 receptors alter BrdU incorporation, another group examined receptor-induced changes in cell cycle protein expression. Indeed, D1-like receptor activation promotes downregulation of cyclin D and upregulation of the cyclin dependent kinase inhibitor p27Kip1. Cyclin D promotes the transition from the growth phase to S-phase of the cell cycle while p27Kip1 inhibits it. In addition, Raf-1, a component of the mitogen-activated protein kinase (MAPK) pathway that promotes mitosis, is downregulated by D1-like receptor activation. The mechanism by which these effects on cell cycle proteins occur is not known, although it appears to be PKA-independent. The effects of transient differences in cell cycle proteins have yet to be understood, but small deviations in the number of cells available to release or receive important developmental signals could significantly alter developmental trajectory. And although it is beyond the scope of our current review, it is also worth noting that both acute and chronic DA depletion decreases subependymal neuronal proliferation, and DA receptors, especially D3 receptors, can guide adult neurogenesis as well.

13As mentioned above, inappropriate excitation-inhibition balance in frontal cortex is found in several neuropsychiatric diseases, which could be partly due to a lack of adequate interneuron migration. The two main cell types in the frontal cortex, glutamatergic pyramidal projection neurons and GABAergic interneurons, are derived from two separate progenitor pools in the developing rodent forebrain. Pyramidal neurons are produced locally in the neuroepithelium of the developing cortex and migrate radially to the appropriate cortical layer. Concurrently, GABAergic interneurons generated in the basal forebrain in the medial and caudal ganglionic eminences migrate tangentially to the cortex. The number of GABAergic interneurons increases through mammalian brain evolution beyond what the ganglionic eminences can provide. Therefore, in primates, GABAergic interneurons are also produced in the dorsal forebrain and migrate radially through cortex. However, this tangentially migrating population of interneurons is still a substantial portion of interneurons produced, and dysregulation of either population would contribute to neuropsychiatric disease.

14GABAergic neurons in the medial and caudal ganglionic eminences express DA receptors, and these forebrain regions receive DAergic innervation during the embryonic period when migration occurs. The Bhide lab has demonstrated that altering DA receptor signaling with prenatal cocaine or receptor-specific agonists/antagonists disrupts tangential migration (illustrated in Figure 1A). Prenatal cocaine exposure decreases tangential migration of cortical GABAergic neurons, perhaps mediated by the loss of D1 receptor signaling. In addition, application of D1-like receptor agonists in mouse embryonic slice cultures promotes cortical GABAergic neuron migration whereas D2-like receptor agonism decreases migration. Overexpression of the D1 receptor by in vitro electroporation increases the effect of D1-like receptor agonists on promoting tangential migration. The basis for opposing D1 vs. D2 receptor effects is not fully understood, but cytoskeletal reorganization must occur for neuronal migration. D1-like receptor stimulation leads to increased neurite localization of cytoskeletal elements needed for cell motility, such as cytoplasmic dynein motor protein and tubulin, whereas D2-like receptor stimulation leads to increased cell body localization of these cytoskeletal elements. suggest that this subtype-specific redistribution of cytoskeletal elements needed for cell motility leads to opposite effects on neuronal migration. Elucidation of the molecular pathways responsible for receptor-dependent modulation of neuronal migration may provide new targets for the restoration of neurodevelopmental trajectory.

15Dendritic and axonal growth are activity-dependent, highly dynamic processes that remain partially plastic until adulthood. Disruption of dendritic or axonal growth alters both the quantity and nature of neural connections. Not surprisingly, anomalies in brain connectivity have been linked to several neuropsychiatric diseases, including intellectual disability and schizophrenia. In fact, DA receptor activation modulates dendritic structure, creating subtle but significant changes in brain architecture that may increase vulnerability to neurological and/or neuropsychiatric disease.

16In this regard, activation of DA receptors influences axonal and dendritic growth in a subtype-specific manner. Primary cultures have been the primary model to test the in vitro effects of DAergic modulation on neurite outgrowth, a term to describe both the developing axon and dendrite. Several groups demonstrated that D1-like receptor agonists significantly reduce neurite outgrowth in frontal cortical neuronal cultures, which is depicted in Figure 1B. further observed that decreased neurite outgrowth is associated with destabilization of dendritic microtubule associated protein (MAP2) by increased phosphorylation. Increased MAP2 phosphorylation is commonly associated with decreased neurite outgrowth. However, activation of numerous kinases causes MAP2 phosphorylation, providing an effector but not the mechanism. An animal model of prenatal cocaine exposure also demonstrates the importance of cortical D1 receptor signaling to suppress neurite outgrowth. This model produces a long-lasting uncoupling of D1 receptor signaling and concomitant increase in neurite outgrowth. Our group has also observed increased basal neurite outgrowth in cortical cultures derived from D1 receptor null embryos as compared to cultures derived from wild-type littermates (unpublished data). With regards to axonal effects, evidence suggests that D1-like receptor stimulation also alters cortical axon growth patterns by decreasing expression of the netrin-1 receptor. In contrast to the growth-suppressing effects of D1-like receptor stimulation, D2-like receptor activation in primary cortical cultures leads to an increase in neurite outgrowth (illustrated in Figure 1B;; ). Thus, D1-like receptor stimulation decreases neurite outgrowth and netrin-1 receptor expression whereas D2-like receptor stimulation increases neurite outgrowth in vitro. Yet, the DA receptor-expressing population is only approximately 10–15% of neurons in the frontal cortex. Ongoing research in our group is testing whether these effects are cell-specific (only occurring in neurons expressing DA receptors) or if a non-cell specific mechanism leads to DA receptor-induced changes on neurite outgrowth in other subpopulations.

17In contrast, application of D1-like receptor agonists to striatal neuronal cultures promotes neurite outgrowth, which can be blocked with D1-like receptor antagonists and is demonstrated in Figure 1B. This increased neurite outgrowth is associated with an increased number of growth cones and arborization. However, D2-like receptor activation shows no effect on striatal neurite outgrowth (also demonstrated in Figure 1B; ). Hence, D1-like receptor stimulation increases neurite outgrowth in the striatum in vitro.

18Studies from intact brains bolster the importance of developmental DA receptor signaling on dendritic growth in DA-rich brain regions. Models of DA depletion (i.e., 6-OHDA treatment or mesencephalic lesion) show decreased expression of axon guidance- and cytoskeletal growth-related proteins as well as decreased length of pyramidal layer V basal dendrites in frontal cortex. In human studies, adolescents exposed prenatally to cocaine display changes in cortical thickness. MAP2 labeling of D1 receptor knockout mice and diolistic labeling of rabbits prenatally exposed to cocaine show abnormal apical dendrites of cortical pyramidal cells with decreased bundling and increased tortuous patterning, which supports the increased basal neurite outgrowth observed in vitro. Conversely, silver impregnation of cortical neurons from D1 receptor overexpressing mice show decreased apical dendrite length compared to wild type littermates, which further supports a role for D1 receptor signaling to promote dendritic growth. Finally, the Kellendonk lab has shown that mice overexpressing D2 receptors in the striatum have decreased complexity and length of striatal dendritic arbors. Although differences in normal striatal dendritic morphology have been studied based on receptor subtype expression, to our knowledge the effects of reduced or absent D1 receptor signaling on striatal dendritic morphology has not been examined.

19Dendritic spinous processes start to form at the beginning of synaptogenesis during the first postnatal week and peak in adolescence but continue to be structurally modified throughout adulthood. Spines develop from dendritic filopodia that interact with incoming axons, but some data suggest that dendritic spines can form independent of axonal interaction. Dendritic spines are critical for synaptic plasticity, allowing for compartmentalization of post-synaptic signaling and synaptic specialization. Additionally, alterations in spine density likely originating during development are found in many neuropsychiatric diseases, such as autism and schizophrenia. Importantly, DA plays a role in spinogenesis. For example, a functional hyperdopaminergia, which occurs in DA transporter (DAT) knockout mice, leads to a loss of proximal dendritic spines in striatal projection neurons. This model also shows a behavioral phenotype of hyperactivity and anxiety as well as altered mesocortical circuitry, and DA dysregulation occurs not only during development, but continues into adulthood in this model. Primate and rodent models of DA depletion also show decreases in striatal dendritic spines. Thus, a delicate balance of DA signaling is required for formation/stabilization of dendritic spines. Cortical pyramidal neurons of D1 and D2 receptor knockout mice exhibit decreased dendritic spine density, and moderate D1-like and D2-like receptor activation both have been shown to increase spine density and spinophillin expression in the striatum in vitro. Studies have not yet shown if higher concentrations of DAergic agonists, more like the activation levels seen in the hyperdopaminergic DAT knockout mouse, would phenocopy the decreased dendritic spine density seen in that (potentially non-physiological) mutant. In fact, during adolescence D2 receptor activation decreases striatal dendritic spines. Interestingly, the spine loss in cortical pyramidal neurons resulting from DA depletion can be ameliorated by spinogenesis-promoting antipsychotics like clozapine, providing further support for spine dysfunction in the pathology of neuropsychiatric disease.

20Since dendritic spines serve as the recipients of synaptic input and both develop concurrently, spinogenesis and synaptogenesis are intimately connected and are often co-regulated. Multiple points of vulnerability beyond spine formation can be altered to disrupt synaptogenesis. Axonal pathfinding must lead to the vicinity of the target neuron for initial contact to be made. Cell-cell adhesion then needs to occur, followed by pre- and post-synaptic differentiation and synapse strengthening. Synapse formation, when it occurs properly, leads to the formation of connections on a particular part (usually dendritic spines) of a target neuron, sometimes over very long distances. Schizophrenia and other neurodevelopmental disorders are at least in part, diseases of altered synaptic connectivity. Inappropriate dendritic arborization, spinogenesis, and synaptic connections lead to inappropriate connectivity and altered excitation-inhibition balance. This is supported by observations of decreased dendritic spines and synaptic labeling in post mortem cortex of schizophrenic patients. Thus, synaptogenesis can be altered by any of the previously discussed developmental events and plays an important role in neuropsychiatric disease pathology.

21Synaptogenesis follows a similar timeline of development as spinogenesis and displays similar responses to DAergic modulation. Synapses begin to form during the first postnatal week. The number of synapses peak during adolescence, which is followed by synaptic pruning. In the striatum and frontal cortex, electron microscopy has shown that DAergic axons form symmetric synapses similar to most GABAergic interneurons whereas glutamatergic pyramidal axons forms asymmetric synapses. Neonatal DA depletion decreases the number of symmetric synapses and changes the structure of asymmetric synapses. Others have suggested that neonatal DA depletion can alter dendritic structures in the frontal cortex, and cause dysregulation of gene expression patterns required for normal brain architecture. DA receptor antagonists can decrease prefrontal synapse density whereas agonists slightly increased density. Furthermore, haloperidol, a D2-like receptor antagonist, decreases hippocampal synaptic density in vitro. Opposing D1 vs. D2 receptor developmental effects are lost with regards to spinogenesis and synaptogenesis, and hopefully further study will produce a mechanistic explanation. DA lesion studies in adult animals support a continued role for DA in the maintenance of corticostriatal synapses in the striatum (for a comprehensive review of DA-regulated morphological and electrophysiological changes, please see and ). Taken together, these studies support a crucial role for DA in formation and stabilization of synaptic connections in the striatum and frontal cortex, providing further evidence for developmental disruptions of DA and other neurotransmitters in the structural pathology of neuropsychiatric disease.

22Establishing a detailed signaling mechanism for the above mentioned in vitro and in vivo effects on developmental processes is complicated by multiple signaling cascades and receptor interactions. While all five DA receptors likely contribute to these effects in specific ways, studies to date have predominantly examined D1 receptors, and thus our discussion will also focus there. In general, D1-like receptors transduce their signals by activating adenylyl cyclase and increasing intracellular cAMP via Gαs/Gαolf coupled proteins. Conversely, D2-like receptors typically transduce their signals by inhibiting adenylyl cyclase and decreasing cAMP. Intracellular cAMP activates protein kinase A (PKA), which phosphorylates proteins such as DA and cAMP-regulated phosphoprotein (DARPP-32) and cAMP responsive-element binding protein (CREB;; ). CREB promotes transcription of genes with cAMP response elements. Additionally, MAPKs like extracellular signal-related kinase (ERK) are activated by D1 receptor stimulation and increase CREB signaling.

23DA receptors also participate in multiple non-Gα protein signaling mechanisms. DA receptor mediated effects can involve Gβ/Gγ proteins as well as other receptors. For example, D1 receptors interact with NMDA receptors, adenosine receptors, and neurotrophin TrkB receptors, among others. D2 receptors complex with adenosine A2A receptors and sigma-1 receptors and recruit protein kinase B/glycogen synthase kinase 3 (AKT/GSK3) signaling pathways via a slower, cAMP-independent signaling mechanism. G protein-coupled receptor kinases and arrestins, normally associated with receptor desensitization, form a scaffold for D2 receptor interactions with protein phosphatase 2A and AKT. The resulting dephosphorylation of AKT increases activity of GSK3, a target of lithium and many antipsychotic drugs.

24Given the profound differences between how neurites of cortical and striatal neurons respond to DA receptor agonists, it is likely that intracellular signals are regulated in cell-specific ways. These are difficult experiments to carry out, however, and we currently have a fairly superficial understanding of these mechanisms. Both D1-like receptor agonists and PKA activators increase cortical MAP2 phosphorylation, decreasing the ability of MAP2 to stabilize the dendritic cytoskeleton and thus decreasing neurite outgrowth. Neurite outgrowth facilitation by D1-like receptor stimulation in the striatum is also PKA-dependent and at least in part CREB-mediated. Additionally, the Chao lab has demonstrated that increased neurite outgrowth in striatal cultures is at least partially dependent on D1 receptor-mediated neurotrophin TrkB receptor activation. Their study showed that D1-like receptor agonist treatment in primary striatal cultures leads to activation and increased surface expression of the TrkB receptor, and is accompanied by phosphorylation of downstream Trk signaling proteins. Thus, taken together, current evidence suggests that the D1-like receptor-mediated changes in neurite outgrowth are PKA-dependent in both cortex and striatum with an additional neurotrophin TrkB receptor-dependent component only in the striatum. The dichotomy between D1 and D2 receptor signaling in the context of developmental dysfunction needs to be understood in order to target the neurodevelopmental origins of neuropsychiatric disease. Furthermore, future studies should identify potential roles for differences in G protein coupling (e.g., Gαs in cortex and Gαolf in striatum; ), and accessory proteins with differential expression patterns (e.g., GPR88 in striatum;; ).

25The DA system plays a fundamental role in psychotic disorders, with D2 receptor antagonism being a major target for both typical and atypical antipsychotics. While D2 receptor antagonism may be useful in controlling many of the positive symptoms in schizophrenia, emerging data implicates D1-like receptors as a target for negative symptoms in schizophrenia. In addition, several genetic perturbations in DA-related genes have been found in patients with neuropsychiatric disease. Patients with 22q11 deletion syndrome, which disrupts DA-related genes (e.g., catechol-O-methyltransferase, COMT) among others have an increased risk for neuropsychiatric disorders, including schizophrenia-like psychosis, autism, and anxiety disorders. Hypomethylation of the COMT gene, which leads to an increase in the enzyme that breaks down DA, has been associated with schizophrenia and bipolar disorder. The translocation in the gene disrupted in schizophrenia-1 (DISC-1) was originally found in a large Scottish family with abnormally high rates of neuropsychiatric disease. Interestingly, knockdown of DISC-1 in animal models causes altered DAergic maturation and behavioral changes associated with altered prefrontal cortex circuitry, suggesting a role for DA in DISC-1 associated neuropsychiatric disease. Association studies implicate the A1 allele of the Taq1 polymorphism of DRD2 in the development of Tourette’s syndrome, ADHD, autism, PTSD, and alcoholism. The Holden lab has found DA-related genes (DRD1, DRD2, and PPP1R1B) associated with the severity of autism in families with males only affected. Others have found polymorphisms in DRD3 and DRD4 associated with autism severity and DAT polymorphisms linked to both ADHD and bipolar disorder. Additionally, polymorphisms in the gene encoding the downstream signaling protein Akt are associated with both bipolar disorder and schizophrenia. While the effect sizes in these studies are not large, and the link to DA is sometimes indirect, taken together these findings emphasize that disrupted DAergic homeostasis may be a central mechanism in the risk of developing a neuropsychiatric disorder.

26There is strong evidence that DA plays a critical role in the generation of typical brain structure and function. DA and its cognate receptors are present in the striatum and frontal cortex early in brain development and contribute to the development of pathways needed for movement, cognition, and reward. Altered DA signaling can affect the proliferation, migration, and differentiation of specific subpopulations of neurons, and thus impact frontal cortex and striatal neurocircuitry. D1 and D2 receptor subtypes often have opposing effects on these developmental processes, and the underlying mechanism for this dichotomy as well as the signaling pathways that mediate these subtype-specific effects remain mostly unknown.

27Yet, DA is not the only neuromodulator that plays a role in developmental processes. Serotonin is present before synaptogenesis and alters neurite outgrowth and axon pathfinding in vitro in a receptor-dependent manner (;;;;;;; for comprehensive review of roles of serotonin in development, see;;; ). In addition, decreased cortical thickness in reelin mutants is postulated to be driven by cortical cholinergic deprivation, and both nicotinic and muscarinic cholinergic receptor manipulation alters neurite outgrowth (;;; for comprehensive review, see;; ). Finally, noradrenergic neurons are thought form early synapses in the cortical plate and mediate neuronal migration and laminar formation. DA thus does not provide a singular role in these developmental processes, and future studies will need to address additional neuromodulators in combinatorial patterns.

28Our understanding of the role of developmental disruptions of DA in the pathology of neuropsychiatric disorders is still maturing. DA-rich areas, such as the prefrontal cortex and striatum, are clearly dysfunctional in neuropsychiatric disorders like schizophrenia, substance use disorders, and ADHD. Developmental alterations in dendritic growth and/or GABAergic interneuron migration likely contribute to the development of pathology in these disorders. The increased DAergic influence in the cortex of primates and dysfunction of DA-rich cortical areas in neuropsychiatric disorders suggests an evolutionally increased role of DA, which has also resulted in an evolutionarily increased vulnerability to disease. A new era of neuropsychiatric pharmacologic targets should address the underlying pathology resulting from developmental disruptions in DA and other neurotransmitters. Importantly, early interventions have the most positive impacts in neurodevelopmental disorders and learning disabilities; our hope is that a detailed mechanistic understanding of brain substrates and developmental pharmacology will allow clinicians to make similar rational interventions within neuropsychiatry.

29The 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.