Presynaptic NMDA Receptors: Newly Appreciated Roles in Cortical Synaptic Function and Plasticity

Abstract

Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDAtype glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the past 10 years demonstrates that NMDARs also exist presynaptically and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here the authors review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. They discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology.

Keywords

Presynaptic NMDA receptors Timing-dependent long-term depression Spike timing-dependent plasticity Cortex Development

Get full access to this article

View all access options for this article.

References

Allen CB , Celikel T. , Feldman DE 2003. Long-term depression induced by sensory deprivation during cortical map plasticity in vivo. Nat Neurosci 6:291-9.

Aoki C. , Venkatesan C. , Go CG , Mong JA , Dawson TM 1994. Cellular and subcellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats. J Neurosci 14: 5202-22.

Avanzini G. , Franceschetti S. 2003. Cellular biology of epileptogenesis. Lancet Neurol 2:33-42.

Awatramani GB , Price GD , Trussell LO 2005. Modulation of transmitter release by presynaptic resting potential and background calcium levels. Neuron 48:109-21.

Bardoni R. , Torsney C. , Tong CK , Prandini M. , MacDermott AB 2004. Presynaptic NMDA receptors modulate glutamate release from primary sensory neurons in rat spinal cord dorsal horn. J Neurosci 24:2774-81.

Bender VA , Bender KJ , Brasier DJ , Feldman DE 2006. Two coincidence detectors for spike timing-dependent plasticity in somatosensory cortex. J Neurosci 26:4166-77.

Berretta N. , Jones RS 1996. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience 75:339-44.

Bezzi P. , Carmignoto G. , Pasti L. , Vesce S. , Rossi D. , Rizzini BL , and others. 1998. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281-5.

Bezzi P. , Domercq M. , Brambilla L. , Galli R. , Schols D. , De Clercq E. , and others. 2001. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702-10.

10.

Bezzi P. , Gundersen V. , Galbete JL , Seifert G. , Steinhauser C. , Pilati E. , Volterra A. 2004. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7:613-20.

11.

Bliss TV , Collingridge GL 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31-9.

12.

Bolshakov VY , Siegelbaum SA 1995. Regulation of hippocampal transmitter release during development and long-term potentiation. Science 269:1730-4.

13.

Brasier DJ , Feldman DE 2008. Synapse-specific expression of functional presynaptic NMDA receptors in rat somatosensory cortex. J Neurosci 28:2199-211.

14.

Carmignoto G. , Vicini S. 1992. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258:1007-11.

15.

Casado M. , Dieudonne S. , Ascher P. 2000. Presynaptic N-methyl-D-aspartate receptors at the parallel fiber-Purkinje cell synapse. Proc Natl Acad Sci U S A 97:11593-7.

16.

Casado M. , Isope P. , Ascher P. 2002. Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression. Neuron 33:123-30.

17.

Catterall WA 1998. Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24:307-23.

18.

Cavelier P. , Attwell D. 2005. Tonic release of glutamate by a DIDSsensitive mechanism in rat hippocampal slices. J Physiol 564:397-410.

19.

Celikel T. , Szostak VA , Feldman DE 2004. Modulation of spike timing by sensory deprivation during induction of cortical map plasticity. Nat Neurosci 7:534-41.

20.

Charton JP , Herkert M. , Becker CM , Schroder H. 1999. Cellular and subcellular localization of the 2B-subunit of the NMDA receptor in the adult rat telencephalon. Brain Res 816:609-17.

21.

Chen HS , Lipton SA 2006. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 97:1611-26.

22.

Chevaleyre V. , Takahashi KA , Castillo PE 2006. Endocannabinoid-mediated synaptic plasticity in the CNS . Annu Rev Neurosci 29:37-76.

23.

Choi S. , Lovinger DM 1997. Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc Natl Acad Sci U S A 94:2665-70.

24.

Collingridge GL , Bliss TV 1995. Memories of NMDA receptors and LTP. Trends Neurosci 18:54-6.

25.

Contractor A. , Swanson G. , Heinemann SF 2001. Kainate receptors are involved in short- and long-term plasticity at mossy fiber synapses in the hippocampus. Neuron 29:209-16.

26.

Corlew R. , Wang Y. , Ghermazien H. , Erisir A. , Philpot BD 2007. Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression. J Neurosci 27:9835-45.

27.

Crozier RA , Wang Y. , Liu CH , Bear MF 2007. Deprivation-induced synaptic depression by distinct mechanisms in different layers of mouse visual cortex. Proc Natl Acad Sci U S A 104:1383-8.

28.

Cull-Candy S. , Brickley S. , Farrant M. 2001. NMDA receptor subunits: diversity, development and disease . Curr Opin Neurobiol 11:327-35.

29.

Dalby NO , Mody I. 2001. The process of epileptogenesis: a pathophysiological approach . Curr Opin Neurol 14:187-92.

30.

Dan Y. , Poo MM 2006. Spike timing-dependent plasticity: from synapse to perception . Physiol Rev 86:1033-48.

31.

DeBiasi S. , Minelli A. , Melone M. , Conti F. 1996. Presynaptic NMDA receptors in the neocortex are both auto- and heteroreceptors. Neuroreport 7:2773-6.

32.

Dekay JG , Chang TC , Mills N. , Speed HE , Dobrunz LE 2006. Responses of excitatory hippocampal synapses to natural stimulus patterns reveal a decrease in short-term facilitation and increase in short-term depression during postnatal development. Hippocampus 16:66-79.

33.

Dingledine R. , Borges K. , Bowie D. , Traynelis SF 1999. The glutamate receptor ion channels. Pharmacol Rev 51:7-61.

34.

Duguid I. , Sjöström PJ 2006. Novel presynaptic mechanisms for coincidence detection in synaptic plasticity. Curr Opin Neurobiol 16:312-22.

35.

Duguid IC , Smart TG 2004. Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron-Purkinje cell synapses. Nat Neurosci 7:525-33.

36.

Egger V. , Feldmeyer D. , Sakmann B. 1999. Coincidence detection and changes of synaptic efficacy in spiny stellate neurons in rat barrel cortex. Nat Neurosci 2:1098-105.

37.

Engelman HS , MacDermott AB 2004. Presynaptic ionotropic receptors and control of transmitter release. Nat Rev Neurosci 5:135-45.

38.

Fan MM , Raymond LA 2007. N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog Neurobiol 81:272-93.

39.

Farb CR , Aoki C. , Ledoux JE 1995. Differential localization of NMDA and AMPA receptor subunits in the lateral and basal nuclei of the amygdala: a light and electron microscopic study. J Comp Neurol 362:86-108.

40.

Feldman DE 2000. Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex. Neuron 27:45-56.

41.

Felmy F. , Neher E. , Schneggenburger R. 2003. Probing the intracellular calcium sensitivity of transmitter release during synaptic facilitation. Neuron 37:801-11.

42.

Fiszman ML , Barberis A. , Lu C. , Fu Z. , Erdelyi F. , Szabo G. , Vicini S. 2005. NMDA receptors increase the size of GABAergic terminals and enhance GABA release. J Neurosci 25:2024-31.

43.

Frenkel MY , Bear MF 2004. How monocular deprivation shifts ocular dominance in visual cortex of young mice. Neuron 44:917-23.

44.

Froemke RC , Dan Y. 2002. Spike-timing-dependent synaptic modification induced by natural spike trains. Nature 416:433-8.

45.

Froemke RC , Poo MM , Dan Y. 2005. Spike-timing-dependent synaptic plasticity depends on dendritic location. Nature 434:221-5.

46.

Fujisawa S. , Aoki C. 2003. In vivo blockade of N-methyl-D-aspartate receptors induces rapid trafficking of NR2B subunits away from synapses and out of spines and terminals in adult cortex. Neuroscience 121:51-63.

47.

Glitsch M. , Marty A. 1999. Presynaptic effects of NMDA in cerebellar Purkinje cells and interneurons. J Neurosci 19:511-9.

48.

Glitsch MD 2008. Calcium influx through N-methyl-d-aspartate receptors triggers GABA release at interneuron-Purkinje cell synapse in rat cerebellum . Neuroscience 151:403-9.

49.

Gogas KR 2006. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol 6:68-74.

50.

Hashimotodani Y. , Ohno-Shosaku T. , Tsubokawa H. , Ogata H. , Emoto K. , Maejima T. , and others. 2005. Phospholipase Cbeta serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal. Neuron 45:257-68.

51.

He HY , Hodos W. , Quinlan EM 2006. Visual deprivation reactivates rapid ocular dominance plasticity in adult visual cortex. J Neurosci 26:2951-5.

52.

Heinbockel T. , Brager DH , Reich CG , Zhao J. , Muralidharan S. , Alger BE , Kao JP 2005. Endocannabinoid signaling dynamics probed with optical tools. J Neurosci 25:9449-59.

53.

Heresco-Levy U. , Javitt DC 1998. The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes . Eur Neuropsychopharmacol 8:141-52.

54.

Herman MA , Jahr CE 2007. Extracellular glutamate concentration in hippocampal slice . J Neurosci 27:9736-41.

55.

Hestrin S. 1992. Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse. Nature 357:686-9.

56.

Humeau Y. , Shaban H. , Bissiere S. , Luthi A. 2003. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426:841-5.

57.

Jo J. , Ball SM , Seok H. , Oh SB , Massey PV , Molnar E. , and others. 2006. Experience-dependent modification of mechanisms of long-term depression. Nat Neurosci 9:170-2.

58.

Jourdain P. , Bergersen LH , Bhaukaurally K. , Bezzi P. , Santello M. , Domercq M. , and others. 2007. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10:331-9.

59.

Kew JN , Richards JG , Mutel V. , Kemp JA 1998. Developmental changes in NMDA receptor glycine affinity and ifenprodil sensitivity reveal three distinct populations of NMDA receptors in individual rat cortical neurons. J Neurosci 18:1935-43.

60.

Khakh BS , Henderson G. 2000. Modulation of fast synaptic transmission by presynaptic ligand-gated cation channels. J Auton Nerv Syst 81:110-21.

61.

Kim DK , Catterall WA 1997. Ca2+-dependent and -independent interactions of the isoforms of the alpha1A subunit of brain Ca2+ channels with presynaptic SNARE proteins . Proc Natl Acad Sci U S A 94:14782-6.

62.

Koester HJ , Sakmann B. 1998. Calcium dynamics in single spines during coincident pre- and postsynaptic activity depend on relative timing of back-propagating action potentials and subthreshold excitatory postsynaptic potentials. Proc Natl Acad Sci U S A 95:9596-601.

63.

Kristiansen LV , Huerta I. , Beneyto M. , Meador-Woodruff JH 2007. NMDA receptors and schizophrenia. Curr Opin Pharmacol 7:48-55.

64.

Lau CG , Zukin RS 2007. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8:413-26.

65.

Lauri SE , Vesikansa A. , Segerstrale M. , Collingridge GL , Isaac JT , Taira T. 2006. Functional maturation of CA1 synapses involves activity-dependent loss of tonic kainate receptor-mediated inhibition of glutamate release. Neuron 50:415-29.

66.

Laurie DJ , Seeburg PH 1994. Ligand affinities at recombinant N-methyl-D-aspartate receptors depend on subunit composition. Eur J Pharmacol 268:335-45.

67.

Le Meur K. , Galante M. , Angulo MC , Audinat E. 2007. Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J Physiol 580:373-83.

68.

Li YH , Han TZ 2007. Glycine binding sites of presynaptic NMDA receptors may tonically regulate glutamate release in the rat visual cortex. J Neurophysiol 97:817-23.

69.

Li YH , Han TZ , Meng K. 2008. Tonic facilitation of glutamate release by glycine binding sites on presynaptic NR2B-containing NMDA autoreceptors in the rat visual cortex. Neurosci Lett 432:212-16.

70.

Liu H. , Mantyh PW , Basbaum AI 1997. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721-4.

71.

Liu H. , Wang H. , Sheng M. , Jan LY , Jan YN , Basbaum AI 1994. Evidence for presynaptic N-methyl-D-aspartate autoreceptors in the spinal cord dorsal horn. Proc Natl Acad Sci U S A 91:8383-7.

72.

Lu CR , Willcockson HH , Phend KD , Lucifora S. , Darstein M. , Valtschanoff JG , Rustioni A. 2005. Ionotropic glutamate receptors are expressed in GABAergic terminals in the rat superficial dorsal horn. J Comp Neurol 486:169-78.

73.

MacDermott AB , Role LW , Siegelbaum SA 1999. Presynaptic ionotropic receptors and the control of transmitter release. Annu Rev Neurosci 22:443-85.

74.

Magee JC , Johnston D. 1997. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275:209-13.

75.

Malenka RC , Bear MF 2004. LTP and LTD: an embarrassment of riches. Neuron 44:5-21.

76.

Mameli M. , Carta M. , Partridge LD , Valenzuela CF 2005. Neurosteroidinduced plasticity of immature synapses via retrograde modulation of presynaptic NMDA receptors. J Neurosci 25:2285-94.

77.

Markram H. , Lubke J. , Frotscher M. , Roth A. , Sakmann B. 1997. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. J Physiol 500(Pt 2):409-40.

78.

Meldrum BS 1994. The role of glutamate in epilepsy and other CNS disorders . Neurology 44:S14-23.

79.

Missale C. , Fiorentini C. , Busi C. , Collo G. , Spano PF 2006. The NMDA/D1 receptor complex as a new target in drug development . Curr Top Med Chem 6:801-8.

80.

Monyer H. , Burnashev N. , Laurie DJ , Sakmann B. , Seeburg PH 1994. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529-40.

81.

Monyer H. , Sprengel R. , Schoepfer R. , Herb A. , Higuchi M. , Lomeli H. , and others. 1992. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217-21.

82.

Morimoto K. , Fahnestock M. , Racine RJ 2004. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol 73:1-60.

83.

Nevian T. , Sakmann B. 2006. Spine Ca2+ signaling in spike-timing-dependent plasticity . J Neurosci 26:11001-13.

84.

Nosyreva ED , Huber KM 2005. Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression . J Neurosci 25:2992-3001.

85.

Philpot BD , Sekhar AK , Shouval HZ , Bear MF 2001. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29:157-69.

86.

Pickel VM , Colago EE , Mania I. , Molosh AI , Rainnie DG 2006. Dopamine D1 receptors co-distribute with N-methyl-D-aspartic acid type-1 subunits and modulate synaptically-evoked N-methyl-D aspartic acid currents in rat basolateral amygdala. Neuroscience 142:671-90.

87.

Pinheiro PS , Mulle C. 2008. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat Rev Neurosci 9:423-36.

88.

Pinheiro PS , Perrais D. , Coussen F. , Barhanin J. , Bettler B. , Mann JR , and others. 2007. GluR7 is an essential subunit of presynaptic kainate autoreceptors at hippocampal mossy fiber synapses. Proc Natl Acad Sci USA 104:12181-6.

89.

Pouzat C. , Hestrin S. 1997. Developmental regulation of basket/stellate cell-->Purkinje cell synapses in the cerebellum. J Neurosci 17:9104-12.

90.

Priestley T. , Laughton P. , Myers J. , Le Bourdelles B. , Kerby J. , Whiting PJ 1995. Pharmacological properties of recombinant human N-methyl-D-aspartate receptors comprising NR1a/NR2A and NR1a/NR2B subunit assemblies expressed in permanently transfected mouse fibroblast cells. Mol Pharmacol 48:841-8.

91.

Reyes A. , Sakmann B. 1999. Developmental switch in the short-term modification of unitary EPSPs evoked in layer 2/3 and layer 5 pyramidal neurons of rat neocortex . J Neurosci 19:3827-35.

92.

Rodríguez-Moreno A. , Paulsen O. 2008. Spike timing-dependent long-term depression requires presynaptic NMDA receptors. Nat Neurosci 11:744-5.

93.

Rumpel S. , Kattenstroth G. , Gottmann K. 2004. Silent synapses in the immature visual cortex: layer-specific developmental regulation. J Neurophysiol 91:1097-101.

94.

Sah P. , Hestrin S. , Nicoll RA 1989. Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246:815-8.

95.

Sasaki YF , Rothe T. , Premkumar LS , Das S. , Cui J. , Talantova MV , and others. 2002. Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J Neurophysiol 87:2052-63.

96.

Scanziani M. , Gahwiler BH , Charpak S. 1998. Target cell-specific modulation of transmitter release at terminals from a single axon. Proc Natl Acad Sci U S A 95:12004-9.

97.

Shin JH , Linden DJ 2005. An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J Neurophysiol 94:4281-9.

98.

Shouval HZ , Kalantzis G. 2005. Stochastic properties of synaptic transmission affect the shape of spike time-dependent plasticity curves. J Neurophysiol 93:1069-73.

99.

Siegel SJ , Brose N. , Janssen WG , Gasic GP , Jahn R. , Heinemann SF , Morrison JH 1994. Regional, cellular, and ultrastructural distribution of N-methyl-D-aspartate receptor subunit 1 in monkey hippocampus. Proc Natl Acad Sci U S A 91:564-8.

100.

Sjöström PJ , Turrigiano GG , Nelson S. 2003. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron 39:641-54.

101.

Sjöström PJ , Turrigiano GG , Nelson SB 2001. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity. Neuron 32:1149-64.

102.

Strack S. , McNeill RB , Colbran RJ 2000. Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 275:23798-806.

103.

Suarez LM , Solis JM 2006. Taurine potentiates presynaptic NMDA receptors in hippocampal Schaffer collateral axons. Eur J Neurosci 24:405-18.

104.

Suarez LM , Suarez F. , Del Olmo N. , Ruiz M. , Gonzalez-Escalada JR , Solis JM 2005. Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin. Eur J Neurosci 21:197-209.

105.

Sun HY , Dobrunz LE 2006. Presynaptic kainate receptor activation is a novel mechanism for target cell-specific short-term facilitation at Schaffer collateral synapses . J Neurosci 26:10796-807.

106.

Trussell LO 2002. Modulation of transmitter release at giant synapses of the auditory system. Curr Opin Neurobiol 12:400-4.

107.

Turecek R. , Trussell LO 2001. Presynaptic glycine receptors enhance transmitter release at a mammalian central synapse. Nature 411: 587-90.

108.

Valenzuela CF , Partridge LD , Mameli M. , Meyer DA 2008. Modulation of glutamatergic transmission by sulfated steroids: role in fetal alcohol spectrum disorder. Brain Res Rev 57:506-19.

109.

Visser E. , Schug SA 2006. The role of ketamine in pain management. Biomed Pharmacother 60:341-8.

110.

Vitten H. , Isaacson JS 2001. Synaptic transmission: exciting times for presynaptic receptors. Curr Biol 11:R695-7.

111.

Woodhall G. , Evans DI , Cunningham MO , Jones RS 2001. NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. J Neurophysiol 86:1644-51.

112.

Yang J. , Woodhall GL , Jones RS 2006. Tonic facilitation of glutamate release by presynaptic NR2B-containing NMDA receptors is increased in the entorhinal cortex of chronically epileptic rats. J Neurosci 26:406-10.

113.

Yashiro K. , Corlew R. , Philpot BD 2005. Visual deprivation modifies both presynaptic glutamate release and the composition of perisynaptic/extrasynaptic NMDA receptors in adult visual cortex. J Neurosci 25:11684-92.

114.

Yasuda H. , Barth AL , Stellwagen D. , Malenka RC 2003. A developmental switch in the signaling cascades for LTP induction. Nat Neurosci 6:15-6.