Lactate-mediated glia-neuronal signalling in the mammalian brain

Abstract

Astrocytes produce and release L -lactate as a potential source of energy for neurons. Here we present evidence that L -lactate, independently of its caloric value, serves as an astrocytic signalling molecule in the locus coeruleus (LC). The LC is the principal source of norepinephrine to the frontal brain and thus one of the most influential modulatory centers of the brain. Optogenetically activated astrocytes release L -lactate, which excites LC neurons and triggers release of norepinephrine. Exogenous L -lactate within the physiologically relevant concentration range mimics these effects. L -lactate effects are concentration-dependent, stereo-selective, independent of L -lactate uptake into neurons and involve a cAMP-mediated step. In vivo injections of L -lactate in the LC evokes arousal similar to the excitatory transmitter, L -glutamate. Our results imply the existence of an unknown receptor for this ‘glio-transmitter’.

References 63

1. 1.

   Wang F.. Astrocytes modulate neural network activity by Ca(2)+-dependent uptake of extracellular K+. Sci. Signal. 5, ra26 (2012 ).

   Not in our library10.1126/scisignal.2002334

2. 2.

   Henneberger C., Papouin T., Oliet S. H. & Rusakov D. A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010 ).

   Not in our library10.1038/nature08673

3. 3.

   Gordon G. R.. Astrocyte-mediated distributed plasticity at hypothalamic glutamate synapses. Neuron 64, 391–403 (2009 ).

   Not in our library10.1016/j.neuron.2009.10.021

4. 4.

   Gourine A. V.. Astrocytes control breathing through pH-dependent release of ATP. Science 329, 571–575 (2010 ).

   Not in our library10.1126/science.1190721

5. 5.

   Koizumi S., Fujishita K., Tsuda M., Shigemoto-Mogami Y. & Inoue K. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures. Proc. Natl Acad. Sci. USA 100, 11023–11028 (2003 ).

   Not in our library10.1073/pnas.1834448100

6. 6.

   Bowser D. N. & Khakh B. S. ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J. Neurosci. 24, 8606–8620 (2004 ).

   Not in our library10.1523/jneurosci.2660-04.2004

7. 7.

   Parpura V. & Haydon P. G. Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons. Proc. Natl Acad. Sci. USA 97, 8629–8634 (2000 ).

   Not in our library10.1073/pnas.97.15.8629

8. 8.

   Panatier A.. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006 ).

   Not in our library10.1016/j.cell.2006.02.051

9. 9.

   Bouzier-Sore A. K., Voisin P., Canioni P., Magistretti P. J. & Pellerin L. Lactate is a preferential oxidative energy substrate over glucose for neurons in culture. J. Cereb. Blood Flow Metab. 23, 1298–1306 (2003 ).

   Not in our library10.1097/01.wcb.0000091761.61714.25

10. 10.

    Pellerin L.. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev. Neurosci. 20, 291–299 (1998 ).

    Not in our library10.1159/000017324

11. 11.

    Pellerin L. & Magistretti P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. USA 91, 10625–10629 (1994 ).

    Not in our library10.1073/pnas.91.22.10625

12. 12.

    Dienel G. A. Brain lactate metabolism: the discoveries and the controversies. J. Cereb. Blood Flow Metab. 32, 1107–1138 (2012 ).

    Not in our library10.1038/jcbfm.2011.175

13. 13.

    Barros L. F. Metabolic signaling by lactate in the brain. Trends Neurosci. 36, 396–404 (2013 ).

    Not in our library10.1016/j.tins.2013.04.002

14. 14.

    Suzuki A.. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823 (2011 ).

    Not in our library10.1016/j.cell.2011.02.018

15. 15.

    Gibbs M. E. & Hertz L. Inhibition of astrocytic energy metabolism by D-lactate exposure impairs memory. Neurochem. Int. 52, 1012–1018 (2008 ).

    Not in our library10.1016/j.neuint.2007.10.014

16. 16.

    Hall C. N., Klein-Flugge M. C., Howarth C. & Attwell D. Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing. J. Neurosci. 32, 8940–8951 (2012 ).

    Not in our library10.1523/jneurosci.0026-12.2012

17. 17.

    Stone E. A. & Ariano M. A. Are glial cells targets of the central noradrenergic system? A review of the evidence. Brain Res. Rev. 14, 297–309 (1989 ).

    Not in our library10.1016/0165-0173(89)90015-5

18. 18.

    Hertz L., Chen Y., Gibbs M. E., Zang P. & Peng L. Astrocytic adrenoceptors: a major drug target in neurological and psychiatric disorders? Curr. Drug Targets. CNS. Neurol. Disord. 3, 239–267 (2004 ).

    Not in our library10.2174/1568007043337535

19. 19.

    Bekar L. K., He W. & Nedergaard M. Locus coeruleus alpha-adrenergic-mediated activation of cortical astrocytes in vivo. Cereb. Cortex 18, 2789–2795 (2008 ).

    Not in our library10.1093/cercor/bhn040

20. 20.

    Airan R. D., Thompson K. R., Fenno L. E., Bernstein H. & Deisseroth K. Temporally precise in vivo control of intracellular signalling. Nature 458, 1025–1029 (2009 ).

    Not in our library10.1038/nature07926

21. 21.

    Chiu T. H., Chen M. J., Yang Y. R., Yang J. J. & Tang F. I. Action of dexmedetomidine on rat locus coeruleus neurones: intracellular recording in vitro. Eur. J. Pharmacol. 285, 261–268 (1995 ).

    Not in our library10.1016/0014-2999(95)00417-j

22. 22.
    Orexin A activates locus coeruleus cell firing and increases arousal in the rat · 1999

    Not checked
23. 23.

    Walls A. B.. Characterization of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) as an inhibitor of brain glycogen shunt activity. J. Neurochem. 105, 1462–1470 (2008 ).

    Not in our library10.1111/j.1471-4159.2008.05250.x

24. 24.

    Choi H. B.. Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron 75, 1094–1104 (2012 ).

    Not in our library10.1016/j.neuron.2012.08.032

25. 25.

    Halestrap A. P. & Price N. T. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem. J. 343, (Pt 2): 281–299 (1999 ).

    Not in our library

26. 26.

    Wang S., Teschemacher A. G., Paton J. F. & Kasparov S. Mechanism of nitric oxide action on inhibitory GABAergic signaling within the nucleus tractus solitarii. FASEB J. 20, 1537–1539 (2006 ).

    Not in our library10.1096/fj.05-5547fje

27. 27.

    Chan B. S., Endo S., Kanai N. & Schuster V. L. Identification of lactate as a driving force for prostanoid transport by prostaglandin transporter PGT. Am. J. Physiol. Renal Physiol. 282, F1097–F1102 (2002 ).

    Not in our library10.1152/ajprenal.00151.2001

28. 28.

    Gordon G. R., Choi H. B., Rungta R. L., Ellis-Davies G. C. & MacVicar B. A. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008 ).

    Not in our library10.1038/nature07525

29. 29.

    Lin J. Y., Lin M. Z., Steinbach P. & Tsien R. Y. Characterization of engineered channelrhodopsin variants with improved properties and kinetics. Biophys. J. 96, 1803–1814 (2009 ).

    Not in our library10.1016/j.bpj.2008.11.034

30. 30.

    Mastitskaya S.. Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones. Cardiovasc. Res. 95, 487–494 (2012 ).

    Not in our library10.1093/cvr/cvs212

31. 31.

    Wyss M. T., Jolivet R., Buck A., Magistretti P. J. & Weber B. In vivo evidence for lactate as a neuronal energy source. J. Neurosci. 31, 7477–7485 (2011 ).

    Not in our library10.1523/jneurosci.0415-11.2011

32. 32.

    Mukhtarov M., Ivanov A., Zilberter Y. & Bregestovski P. Inhibition of spontaneous network activity in neonatal hippocampal slices by energy substrates is not correlated with intracellular acidification. J. Neurochem. 116, 316–321 (2011 ).

    Not in our library10.1111/j.1471-4159.2010.07111.x

33. 33.

    Nedergaard M. Intracellular Ca2+ transients evoked by lactic acid in cultured mammalian neurons. Am. J. Physiol. 268, R506–R513 (1995 ).

    Not in our library10.1152/ajpregu.1995.268.2.r506

34. 34.

    Song Z. & Routh V. H. Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54, 15–22 (2005 ).

    Not in our library10.2337/diabetes.54.1.15

35. 35.

    Parsons M. P. & Hirasawa M. ATP-sensitive potassium channel-mediated lactate effect on orexin neurons: implications for brain energetics during arousal. J. Neurosci. 30, 8061–8070 (2010 ).

    Not in our library10.1523/jneurosci.5741-09.2010

36. 36.

    Lin R. Y., Vera J. C., Chaganti R. S. & Golde D. W. Human monocarboxylate transporter 2 (MCT2) is a high affinity pyruvate transporter. J. Biol. Chem. 273, 28959–28965 (1998 ).

    Not in our library10.1074/jbc.273.44.28959

37. 37.

    Manning Fox J. E., Meredith D. & Halestrap A. P. Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J. Physiol. 529, (Pt 2): 285–293 (2000 ).

    Not in our library10.1111/j.1469-7793.2000.00285.x

38. 38.

    Nedergaard M. & Goldman S. A. Carrier-mediated transport of lactic acid in cultured neurons and astrocytes. Am. J. Physiol. 265, R282–R289 (1993 ).

    Not in our library10.1152/ajpregu.1993.265.2.r282

39. 39.

    Demestre M., Boutelle M. & Fillenz M. Stimulated release of lactate in freely moving rats is dependent on the uptake of glutamate. J. Physiol. 499, (Pt 3): 825–832 (1997 ).

    Not in our library10.1113/jphysiol.1997.sp021971

40. 40.

    Dienel G. A., Ball K. K. & Cruz N. F. A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover. J. Neurochem. 102, 466–478 (2007 ).

    Not in our library10.1111/j.1471-4159.2007.04595.x

41. 41.

    Chiti Z. & Teschemacher A. G. Exocytosis of norepinephrine at axon varicosities and neuronal cell bodies in the rat brain. FASEB J. 21, 2540–2550 (2007 ).

    Not in our library10.1096/fj.06-7342com

42. 42.

    Teschemacher A. G. & Seward E. P. Bidirectional modulation of exocytosis by angiotensin II involves multiple G-protein-regulated transduction pathways in chromaffin cells. J. Neurosci. 20, 4776–4785 (2000 ).

    Not in our library10.1523/jneurosci.20-13-04776.2000

43. 43.

    Kaneko M. & Takahashi T. Presynaptic mechanism underlying cAMP-dependent synaptic potentiation. J. Neurosci. 24, 5202–5208 (2004 ).

    Not in our library10.1523/jneurosci.0999-04.2004

44. 44.

    Cai T. Q.. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem. Biophys. Res. Commun. 377, 987–991 (2008 ).

    Not in our library10.1016/j.bbrc.2008.10.088

45. 45.

    Ge H.. Elucidation of signaling and functional activities of an orphan GPCR, GPR81. J. Lipid Res. 49, 797–803 (2008 ).

    Not in our library10.1194/jlr.m700513-jlr200

46. 46.

    Liu C.. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284, 2811–2822 (2009 ).

    Not in our library10.1074/jbc.m806409200

47. 47.

    Kuei C.. Study of GPR81, the lactate receptor, from distant species identifies residues and motifs critical for GPR81 functions. Mol. Pharmacol. 80, 848–858 (2011 ).

    Not in our library10.1124/mol.111.074500

48. 48.

    Dienel G. A. & Hertz L. Glucose and lactate metabolism during brain activation. J. Neurosci. Res. 66, 824–838 (2001 ).

    Not in our library10.1002/jnr.10079

49. 49.

    Magistretti P. J., Sorg O., Yu N., Martin J. L. & Pellerin L. Neurotransmitters regulate energy metabolism in astrocytes: implications for the metabolic trafficking between neural cells. Dev. Neurosci. 15, 306–312 (1993 ).

    Not in our library10.1159/000111349

50. 50.

    Fillenz M., Lowry J. P., Boutelle M. G. & Fray A. E. The role of astrocytes and noradrenaline in neuronal glucose metabolism. Acta Physiologica Scandinavica 167, 275–284 (1999 ).

    Not in our library10.1046/j.1365-201x.1999.00578.x

51. 51.

    Duale H., Kasparov S., Paton J. F. R. & Teschemacher A. G. Differences in transductional tropism of adenoviral and lentiviral vectors in the rat brainstem. Exp. Physiol. 90, 71–78 (2005 ).

    Not in our library10.1113/expphysiol.2004.029173

52. 52.

    Campbell R. E.. A monomeric red fluorescent protein. Proc. Natl Acad. Sci. USA 99, 7877–7882 (2002 ).

    Not in our library10.1073/pnas.082243699

53. 53.

    Hwang D. Y., Carlezon W. A. Jr, Isacson O. & Kim K. S. A high-efficiency synthetic promoter that drives transgene expression selectively in noradrenergic neurons. Hum. Gene Ther. 12, 1731–1740 (2001 ).

    Not in our library10.1089/104303401750476230

54. 54.

    Nagel G.. Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Curr. Biol. 15, 2279–2284 (2005 ).

    Not in our library10.1016/j.cub.2005.11.032

55. 55.

    Shcherbo D.. Far-red fluorescent tags for protein imaging in living tissues. Biochem. J. 418, 567–574 (2009 ).

    Not in our library10.1042/bj20081949

56. 56.

    Liu B. H., Paton J. F. R. & Kasparov S. Viral vectors based on bidirectional cell-specific mammalian promoters and transcriptional amplification strategy for use in vitro and in vivo. BMC Biotechnol. 8, 49 (2008 ).

    Not in our library10.1186/1472-6750-8-49

57. 57.

    Figueiredo M.. Optogenetic experimentation on astrocytes. Exp. Physiol. 96, 40–50 (2011 ).

    Not in our library10.1113/expphysiol.2010.052597

58. 58.

    Feinstein P. G.. Molecular cloning and characterization of a Ca2+/calmodulin-insensitive adenylyl cyclase from rat brain. Proc. Natl Acad. Sci. USA 88, 10173–10177 (1991 ).

    Not in our library10.1073/pnas.88.22.10173

59. 59.

    Masada N., Schaks S., Jackson S. E., Sinz A. & Cooper D. M. Distinct mechanisms of calmodulin binding and regulation of adenylyl cyclases 1 and 8. Biochemistry 51, 7917–7929 (2012 ).

    Not in our library10.1021/bi300646y

60. 60.

    Iwatsubo K., Tsunematsu T. & Ishikawa Y. Isoform-specific regulation of adenylyl cyclase: a potential target in future pharmacotherapy. Expert. Opin. Ther. Targets 7, 441–451 (2003 ).

    Not in our library10.1517/14728222.7.3.441

61. 61.

    Teschemacher A. G., Paton J. F. R. & Kasparov S. Imaging living central neurones using viral gene transfer. Adv. Drug Delivery Rev. 57, 79–93 (2005 ).

    Not in our library10.1016/j.addr.2004.05.004

62. 62.

    Marriott D. R., Hirst W. D. & Ljungberg M. C. Astrocytes. inNeural Cell Culture—A Oractical Approach (eds Cohen J., Wilkin G. P. 85–96Oxford University Press (1995 ).

    Not in our library

63. 63.

    Paxinos G. & Watson C. The Rat Brain in Stereotaxic Coordinates Academic Press Ltd. (1986 ).

    Not in our library

Cited by papers we hold 12

• Lactylation, an emerging hallmark of metabolic reprogramming: Current progress and open challenges · 2022
  No notice
• Lactate induces synapse-specific potentiation on CA3 pyramidal cells of rat hippocampus. · 2020
  Not checked
• Stress gates an astrocytic energy reservoir to impair synaptic plasticity · 2020
  Corrected
• Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis · 2020
  No notice
• Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory · 2017
  No notice
• Role of glycogenolysis in memory and learning: regulation by noradrenaline, serotonin and ATP · 2016
  Not checked
• Lactate as a Signaling Molecule That Regulates Exercise-Induced Adaptations · 2016
  No notice
• Mechanisms of chemotherapy-induced behavioral toxicities · 2015
  No notice
• Is L-Lactate a Novel Signaling Molecule in the Brain? · 2015
  No notice
• Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress · 2015
  No notice
• Fluxes of lactate into, from, and among gap junction-coupled astrocytes and their interaction with noradrenaline · 2014
  Not checked
• Neuron-glia networks: integral gear of brain function · 2014
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.