Role of Distinct NMDA Receptor Subtypes at Central Synapses

Most excitatory synapses in the brain use the neurotransmitter glutamate to carry impulses between neurons. During fast transmission, glutamate usually activates a mixture of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic cell. Experimental scrutiny of NMDARs provides insight into their involvement in excitatory synaptic transmission and related processes such as as synaptic plasticity, neural development, and pain perception. There is increasing awareness that subtle variation in NMDAR properties is imparted by specific receptor subunits, and recent studies have started to provide perspective into some of the discrete tasks carried out by individual receptor subtypes. Most excitatory synapses in the brain use the neurotransmitter glutamate to carry impulses between neurons. During fast transmission, glutamate usually activates a mixture of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic cell. NMDA receptors (NMDARs), in particular, have generated a great deal of interest, having been implicated in such processes as synaptic plasticity, neural development, and pain perception. Members of this class of receptors have unique molecular properties that allow them to serve as molecular coincidence detectors and to promote long-term changes in neuronal function. There is increasing awareness that subtle variation in NMDAR properties is imparted by specific receptor subunits. This Review covers recent research that has started to provide perspective into some of the discrete tasks carried out by individual receptor subtypes.

[1]  T. Yagi,et al.  Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit , 1995, Nature.

[2]  M. Sheng,et al.  PDZ domains and the organization of supramolecular complexes. , 2001, Annual review of neuroscience.

[3]  A. Momiyama,et al.  Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord , 2000, The Journal of physiology.

[4]  S. Tonegawa,et al.  Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Venneti,et al.  NMDA and Glutamate Evoke Excitotoxicity at Distinct Cellular Locations in Rat Cortical Neurons In Vitro , 2000, The Journal of Neuroscience.

[6]  H. Betz,et al.  Evidence for a Tetrameric Structure of Recombinant NMDA Receptors , 1998, The Journal of Neuroscience.

[7]  H. Pape,et al.  Contribution of NR2B Subunits to Synaptic Transmission in Amygdaloid Interneurons , 2003, The Journal of Neuroscience.

[8]  E. Molnár,et al.  Assembly intracellular targeting and cell surface expression of the human N-methyl-d-aspartate receptor subunits NR1a and NR2A in transfected cells , 1998, Neuropharmacology.

[9]  D. Feldmeyer,et al.  Functional Correlation of NMDA Receptor ε Subunits Expression with the Properties of Single-Channel and Synaptic Currents in the Developing Cerebellum , 1996, The Journal of Neuroscience.

[10]  Y. Yoshimura,et al.  Two Forms of Synaptic Plasticity with Distinct Dependence on Age, Experience, and NMDA Receptor Subtype in Rat Visual Cortex , 2003, The Journal of Neuroscience.

[11]  A. Hendricson,et al.  Ifenprodil and ethanol enhance NMDA receptor-dependent long-term depression. , 2002, The Journal of pharmacology and experimental therapeutics.

[12]  S. Boyce,et al.  Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn , 1999, Neuropharmacology.

[13]  Stuart G. Cull-Candy,et al.  NMDA-receptor channel diversity in the developing cerebellum , 1994, Nature.

[14]  R. Bardoni,et al.  Presynaptic NMDA Receptors Modulate Glutamate Release from Primary Sensory Neurons in Rat Spinal Cord Dorsal Horn , 2004, The Journal of Neuroscience.

[15]  B. Clark,et al.  Currents evoked in Bergmann glial cells by parallel fibre stimulation in rat cerebellar slices , 1997, The Journal of physiology.

[16]  C. Jahr,et al.  Glutamate transporter currents in bergmann glial cells follow the time course of extrasynaptic glutamate. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Sheng,et al.  Eye opening induces a rapid dendritic localization of PSD-95 in central visual neurons , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Kullmann,et al.  NR2B-Containing Receptors Mediate Cross Talk among Hippocampal Synapses , 2004, The Journal of Neuroscience.

[19]  G. Westbrook,et al.  Mobile NMDA Receptors at Hippocampal Synapses , 2002, Neuron.

[20]  K Williams,et al.  Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. , 1993, Molecular pharmacology.

[21]  D. Feldmeyer,et al.  Identification of a native low‐conductance NMDA channel with reduced sensitivity to Mg2+ in rat central neurones. , 1996, The Journal of physiology.

[22]  M. Mayer,et al.  Structure and function of glutamate receptor ion channels. , 2004, Annual review of physiology.

[23]  P. Ascher,et al.  High-Affinity Zinc Inhibition of NMDA NR1–NR2A Receptors , 1997, The Journal of Neuroscience.

[24]  P. Barber,et al.  The rise and fall of NMDA antagonists for ischemic stroke. , 2004, Current molecular medicine.

[25]  B. Song,et al.  Two N‐methyl‐D‐aspartate receptors in rat dorsal root ganglia with different subunit composition and localization , 2002, The Journal of comparative neurology.

[26]  M. Crair.  Neuronal activity during development: permissive or instructive? , 1999, Current Opinion in Neurobiology.

[27]  P. Jonas,et al.  Ionotropic Glutamate Receptors in the CNS , 1999, Handbook of Experimental Pharmacology.

[28]  C. McBain,et al.  Distinct NMDA Receptors Provide Differential Modes of Transmission at Mossy Fiber-Interneuron Synapses , 2002, Neuron.

[29]  Mark Farrant,et al.  Maturation of EPSCs and Intrinsic Membrane Properties Enhances Precision at a Cerebellar Synapse , 2003, The Journal of Neuroscience.

[30]  Mark Farrant,et al.  NMDA receptor subunits: diversity, development and disease , 2001, Current Opinion in Neurobiology.

[31]  J. Isaacson,et al.  Glutamate-Mediated Extrasynaptic Inhibition Direct Coupling of NMDA Receptors to Ca2+-Activated K+ Channels , 2001, Neuron.

[32]  H. Tse,et al.  Structure–activity analysis of a novel NR2C/NR2D‐preferring NMDA receptor antagonist: 1‐(phenanthrene‐2‐carbonyl) piperazine‐2,3‐dicarboxylic acid , 2004, British journal of pharmacology.

[33]  Philippe Isope,et al.  Involvement of Presynaptic N-Methyl-D-Aspartate Receptors in Cerebellar Long-Term Depression , 2002, Neuron.

[34]  G. Carmignoto,et al.  Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. , 1992, Science.

[35]  E. Shimizu,et al.  Genetic enhancement of learning and memory in mice , 1999, Nature.

[36]  M. Ehlers,et al.  An NMDA Receptor ER Retention Signal Regulated by Phosphorylation and Alternative Splicing , 2001, The Journal of Neuroscience.

[37]  Egidio D'Angelo,et al.  NMDA Receptor 2 (NR2) C-Terminal Control of NR Open Probability Regulates Synaptic Transmission and Plasticity at a Cerebellar Synapse , 2002, The Journal of Neuroscience.

[38]  D. Colquhoun,et al.  Single‐channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors , 1998, The Journal of physiology.

[39]  Hiroto Takahashi,et al.  Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits , 2002, Nature.

[40]  R. Malenka,et al.  An ER retention signal explains differences in surface expression of NMDA and AMPA receptor subunits , 2001, Neuropharmacology.

[41]  S. Schorge,et al.  Studies of NMDA Receptor Function and Stoichiometry with Truncated and Tandem Subunits , 2003, The Journal of Neuroscience.

[42]  Ryosuke Kawakami,et al.  Asymmetrical allocation of NMDA receptor epsilon2 subunits in hippocampal circuitry. , 2003, Science.

[43]  J. Sweatt,et al.  Molecular psychology: roles for the ERK MAP kinase cascade in memory. , 2002, Annual review of pharmacology and toxicology.

[44]  T. Yagi,et al.  Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. , 1995, Nature.

[45]  W. Ju,et al.  Glycine binding primes NMDA receptor internalization , 2003, Nature.

[46]  A. Marty,et al.  Presynaptic Effects of NMDA in Cerebellar Purkinje Cells and Interneurons , 1999, The Journal of Neuroscience.

[47]  N J Sucher,et al.  Assembly with the NR1 Subunit Is Required for Surface Expression of NR3A-Containing NMDA Receptors , 2001, The Journal of Neuroscience.

[48]  S. Traynelis,et al.  Control of Voltage-independent Zinc Inhibition of Nmda Receptors by the Nr1 Subunit , 2022 .

[49]  P. Seeburg,et al.  C-Terminal Truncation of NR2A Subunits Impairs Synaptic But Not Extrasynaptic Localization of NMDA Receptors , 2000, The Journal of Neuroscience.

[50]  M. Bear,et al.  Visual Experience and Deprivation Bidirectionally Modify the Composition and Function of NMDA Receptors in Visual Cortex , 2001, Neuron.

[51]  Z. Fu,et al.  PSD‐95 regulates NMDA receptors in developing cerebellar granule neurons of the rat , 2003, The Journal of physiology.

[52]  Nils Ole Dalby,et al.  Activation of NMDA receptors in rat dentate gyrus granule cells by spontaneous and evoked transmitter release. , 2003, Journal of neurophysiology.

[53]  M. Ehlers,et al.  Activity-Dependent mRNA Splicing Controls ER Export and Synaptic Delivery of NMDA Receptors , 2003, Neuron.

[54]  Alison L. Barth,et al.  NMDAR EPSC kinetics do not regulate the critical period for LTP at thalamocortical synapses , 2001, Nature Neuroscience.

[55]  Ryosuke Kawakami,et al.  Asymmetrical Allocation of NMDA Receptor ε2 Subunits in Hippocampal Circuitry , 2003, Science.

[56]  M. Tymianski,et al.  Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury , 2004, Cellular and Molecular Life Sciences CMLS.

[57]  L. Cathala,et al.  Developmental Profile of the Changing Properties of NMDA Receptors at Cerebellar Mossy Fiber–Granule Cell Synapses , 2000, The Journal of Neuroscience.

[58]  T. Bliss,et al.  Controlling the Ups and Downs of Synaptic Strength , 2004, Science.

[59]  S. Aamodt,et al.  Temporal Correlations between Functional and Molecular Changes in NMDA Receptors and GABA Neurotransmission in the Superior Colliculus , 1997, The Journal of Neuroscience.

[60]  Ian Duguid,et al.  Retrograde activation of presynaptic NMDA receptors enhances GABA release at cerebellar interneuron–Purkinje cell synapses , 2004, Nature Neuroscience.

[61]  R. Morris,et al.  Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein , 1998, Nature.

[62]  B. Sakmann,et al.  NMDAR Channel Segments Forming the Extracellular Vestibule Inferred from the Accessibility of Substituted Cysteines , 1999, Neuron.

[63]  A. Dickenson,et al.  NMDA receptors and central hyperalgesic states , 1991, Pain.

[64]  M Farrant,et al.  Identification of subunits contributing to synaptic and extrasynaptic NMDA receptors in Golgi cells of the rat cerebellum , 2000, The Journal of physiology.

[65]  E. Aizenman,et al.  Functional consequences of NR2 subunit composition in single recombinant N-methyl-D-aspartate receptors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[66]  S. Vicini,et al.  Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. , 1998, Journal of neurophysiology.

[67]  G. Collingridge,et al.  Differential Roles of NR2A and NR2B-Containing NMDA Receptors in Cortical Long-Term Potentiation and Long-Term Depression , 2004, The Journal of Neuroscience.

[68]  Hua Guo,et al.  Alteration in the voltage dependence of NMDA receptor channels in rat dorsal horn neurones following peripheral inflammation , 2001, The Journal of physiology.

[69]  B. Clark,et al.  Activity-Dependent Recruitment of Extrasynaptic NMDA Receptor Activation at an AMPA Receptor-Only Synapse , 2002, The Journal of Neuroscience.

[70]  R. Petralia,et al.  NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex , 2003, Nature Cell Biology.

[71]  S. Ferreira,et al.  Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception , 1994, Neuropharmacology.

[72]  M. Mishina,et al.  Developmental loss of miniature N-methyl-d-aspartate receptor currents in NR2A knockout mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[73]  F. Stephenson,et al.  Appropriate NR1-NR1 Disulfide-linked Homodimer Formation Is Requisite for Efficient Expression of Functional, Cell Surface N-Methyl-D-aspartate NR1/NR2 Receptors* , 2004, Journal of Biological Chemistry.

[74]  J. Diamond,et al.  Synaptically Released Glutamate Activates Extrasynaptic NMDA Receptors on Cells in the Ganglion Cell Layer of Rat Retina , 2002, The Journal of Neuroscience.

[75]  Charu Misra,et al.  NR2B and NR2D Subunits Coassemble in Cerebellar Golgi Cells to Form a Distinct NMDA Receptor Subtype Restricted to Extrasynaptic Sites , 2003, The Journal of Neuroscience.

[76]  M. Crair,et al.  Barrel Cortex Critical Period Plasticity Is Independent of Changes in NMDA Receptor Subunit Composition , 2001, Neuron.

[77]  G. Westbrook,et al.  The Incorporation of NMDA Receptors with a Distinct Subunit Composition at Nascent Hippocampal Synapses In Vitro , 1999, The Journal of Neuroscience.

[78]  K. Sakimura,et al.  Input-specific targeting of NMDA receptor subtypes at mouse hippocampal CA3 pyramidal neuron synapses , 2000, Neuropharmacology.

[79]  Yehezkel Ben-Ari,et al.  The NMDA Receptor Is Coupled to the ERK Pathway by a Direct Interaction between NR2B and RasGRF1 , 2003, Neuron.

[80]  H. Monyer,et al.  NR2A Subunit Expression Shortens NMDA Receptor Synaptic Currents in Developing Neocortex , 1997, The Journal of Neuroscience.

[81]  G. Rumbaugh,et al.  Distinct Synaptic and Extrasynaptic NMDA Receptors in Developing Cerebellar Granule Neurons , 1999, The Journal of Neuroscience.

[82]  G. Kerchner,et al.  Genetic enhancement of inflammatory pain by forebrain NR2B overexpression , 2001, Nature Neuroscience.

[83]  David Attwell,et al.  The Role of Glial Glutamate Transporters in Maintaining the Independent Operation of Juvenile Mouse Cerebellar Parallel Fibre Synapses , 2003, The Journal of physiology.

[84]  D. Feldman,et al.  Experience-Dependent Plasticity and the Maturation of Glutamatergic Synapses , 1998, Neuron.

[85]  Mark F. Bear,et al.  Internalization of ionotropic glutamate receptors in response to mGluR activation , 2001, Nature Neuroscience.

[86]  S. Heinemann,et al.  Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. , 1995, Science.

[87]  Ole P. Ottersen,et al.  Intracellular Domains of NMDA Receptor Subtypes Are Determinants for Long-Term Potentiation Induction , 2003, The Journal of Neuroscience.

[88]  R. S. Jones,et al.  NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. , 2001, Journal of neurophysiology.

[89]  John R Huguenard,et al.  Pathway-Specific Differences in Subunit Composition of Synaptic NMDA Receptors on Pyramidal Neurons in Neocortex , 2003, The Journal of Neuroscience.

[90]  J. Blenis,et al.  ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions , 2004, Microbiology and Molecular Biology Reviews.

[91]  P. Paoletti,et al.  Mapping the Binding Site of the Neuroprotectant Ifenprodil on NMDA Receptors , 2002, The Journal of Neuroscience.

[92]  J. Hell,et al.  A Developmental Change in NMDA Receptor-Associated Proteins at Hippocampal Synapses , 2000, The Journal of Neuroscience.

[93]  H. Bading,et al.  Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways , 2002, Nature Neuroscience.

[94]  S. Oliet,et al.  Control of Glutamate Clearance and Synaptic Efficacy by Glial Coverage of Neurons , 2001, Science.

[95]  P. Stern,et al.  Single channel properties of cloned NMDA receptors in a human cell line: comparison with results from Xenopus oocytes. , 1994, The Journal of physiology.

[96]  P. J. Sjöström,et al.  Neocortical LTD via Coincident Activation of Presynaptic NMDA and Cannabinoid Receptors , 2003, Neuron.

[97]  M. Sheng,et al.  Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity , 2004, Science.

[98]  Masahiko Watanabe,et al.  Impairment of Suckling Response, Trigeminal Neuronal Pattern Formation, and Hippocampal LTD in NMDA Receptor ε2 Subunit Mutant Mice , 1996, Neuron.

[99]  R. Petralia,et al.  Trafficking of NMDA receptors. , 2003, Annual review of pharmacology and toxicology.

[100]  K. Roche,et al.  Molecular determinants of NMDA receptor internalization , 2001, Nature Neuroscience.