NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease

Key Points

  • NMDA receptors (NMDARs) are ion channels gated by the excitatory neurotransmitter glutamate. NMDARs are widespread in the CNS and are essential mediators of synaptic transmission and plasticity.

  • NMDARs exist as multiple subtypes that differ in their molecular (subunit) composition. There are assembled as tetramers composed of two obligatory GluN1 subunits along with two GluN2 or GluN3 subunits, of which there are four (GluN2A–GluN2D) and two subtypes (GluN3A and GluN3B) respectively.

  • Each subunit has a typical modular architecture with two large clamshell-like extracellular domains (the N-terminal domain (NTD) involved in assembly and channel modulation and the agonist-binding domain (ABD)), a transmembrane domain (TMD) and a C-terminal domain (CTD) involved in receptor trafficking and signalling. The NTD and CTD regions are the most divergent and account for much of the functional diversity of NMDARs.

  • Each subunit endows the receptor with distinct biophysical, pharmacological and signalling properties

  • The large extracellular region of the receptor harbours an array of binding sites for small-molecule ligands acting as endogenous or exogenous allosteric modulators. Several of these modulators display strong subunit-selectivity, thus allowing for pharmacological profiling of receptor subunit composition.

  • NMDAR subunit composition is plastic, changing during development and according to neuronal activity. Long-term synaptic plasticity of NMDARs also occurs at mature (adult) synapses and has profound consequences on cell firing and subsequent plasticity.

  • Whether specific receptor subtypes carry out specific tasks in the CNS remains a much debated and challenging issue. In particular, evidence points to tri-heteromeric GluN1/GluN2A/GluN2B receptors as critically involved in 'classical' LTP induction at adult CA3–CA1 synapses.

  • NMDARs are implicated in various neurological and psychiatric conditions. Both hypo- and hyperfunction of NMDAR subpopulations can be deleterious, and there is vivid interest in targeting specific subunits for therapeutic interventions.

Abstract

NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.

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Figure 1: NMDAR subunit diversity, structure and expression.
Figure 2: Subunit composition determines receptor properties.
Figure 3: Activity and experience-dependent switch in NMDAR subunit composition.
Figure 4: Plasticity of the NMDAR component at mature synapses.
Figure 5: Role of tri-heteromeric GluN1/GluN2A/GluN2B receptors in AMPAR-mediated synaptic plasticity.
Figure 6: Contribution of NMDAR subunits to Alzheimer's disease and schizophrenia.

References

  1. 1

    Traynelis, S. F. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62, 405–496 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Lau, C. G. & Zukin, R. S. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Rev. Neurosci. 8, 413–426 (2007).

    CAS  Google Scholar 

  3. 3

    Mony, L., Kew, J. N., Gunthorpe, M. J. & Paoletti, P. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. Br. J. Pharmacol. 157, 1301–1317 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Cull-Candy, S. G. & Leszkiewicz, D. N. Role of distinct NMDA receptor subtypes at central synapses. Sci. STKE 2004, re16 (2004).

    PubMed  Google Scholar 

  5. 5

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

    PubMed  Google Scholar 

  6. 6

    Rumbaugh, G., Prybylowski, K., Wang, J. F. & Vicini, S. Exon 5 and spermine regulate deactivation of NMDA receptor subtypes. J. Neurophysiol. 83, 1300–1306 (2000).

    CAS  PubMed  Google Scholar 

  7. 7

    Vance, K. M., Hansen, K. B. & Traynelis, S. F. GluN1 splice variant control of GluN1/GluN2D NMDA receptors. J. Physiol. 590, 3857–3875 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Horak, M. & Wenthold, R. J. Different roles of C-terminal cassettes in the trafficking of full-length NR1 subunits to the cell surface. J. Biol. Chem. 284, 9683–9691 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Watanabe, M., Inoue, Y., Sakimura, K. & Mishina, M. Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport 3, 1138–1140 (1992).

    CAS  PubMed  Google Scholar 

  10. 10

    Akazawa, C., Shigemoto, R., Bessho, Y., Nakanishi, S. & Mizuno, N. Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J. Comp. Neurol. 347, 150–160 (1994).

    CAS  PubMed  Google Scholar 

  11. 11

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

    CAS  PubMed  Google Scholar 

  12. 12

    Laurie, D. J. & Seeburg, P. H. Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J. Neurosci. 14, 3180–3194 (1994).

    CAS  PubMed  Google Scholar 

  13. 13

    Sheng, M., Cummings, J., Roldan, L. A., Jan, Y. N. & Jan, L. Y. Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368, 144–147 (1994).

    CAS  PubMed  Google Scholar 

  14. 14

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

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

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

    CAS  PubMed  Google Scholar 

  16. 16

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

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Rauner, C. & Kohr, G. Triheteromeric NR1/NR2A/NR2B receptors constitute the major N-methyl-D-aspartate receptor population in adult hippocampal synapses. J. Biol. Chem. 286, 7558–7566 (2011).

    CAS  PubMed  Google Scholar 

  18. 18

    Gray, J. A. et al. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo. Neuron 71, 1085–1101 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Chatterton, J. E. et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415, 793–798 (2002).

    CAS  PubMed  Google Scholar 

  20. 20

    Pina-Crespo, J. C. et al. Excitatory glycine responses of CNS myelin mediated by NR1/NR3 “NMDA” receptor subunits. J. Neurosci. 30, 11501–11505 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Fritschy, J. M., Weinmann, O., Wenzel, A. & Benke, D. Synapse-specific localization of NMDA and GABAA receptor subunits revealed by antigen-retrieval immunohistochemistry. J. Comp. Neurol. 390, 194–210 (1998).

    CAS  PubMed  Google Scholar 

  22. 22

    Shinohara, Y. et al. Left-right asymmetry of the hippocampal synapses with differential subunit allocation of glutamate receptors. Proc. Natl Acad. Sci. USA 105, 19498–19503 (2008).

    CAS  PubMed  Google Scholar 

  23. 23

    Zhang, J. & Diamond, J. S. Subunit- and pathway-specific localization of NMDA receptors and scaffolding proteins at ganglion cell synapses in rat retina. J. Neurosci. 29, 4274–4286 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Kumar, S. S. & Huguenard, J. R. Pathway-specific differences in subunit composition of synaptic NMDA receptors on pyramidal neurons in neocortex. J. Neurosci. 23, 10074–10083 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Lei, S. & McBain, C. J. Distinct NMDA receptors provide differential modes of transmission at mossy fiber-interneuron synapses. Neuron 33, 921–933 (2002).

    CAS  PubMed  Google Scholar 

  26. 26

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

    CAS  Google Scholar 

  27. 27

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

    CAS  PubMed  Google Scholar 

  28. 28

    Lopez de Armentia, M. & Sah, P. Development and subunit composition of synaptic NMDA receptors in the amygdala: NR2B synapses in the adult central amygdala. J. Neurosci. 23, 6876–6883 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

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

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Petralia, R. S. et al. Organization of NMDA receptors at extrasynaptic locations. Neuroscience 167, 68–87 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Logan, S. M., Partridge, J. G., Matta, J. A., Buonanno, A. & Vicini, S. Long-lasting NMDA receptor-mediated EPSCs in mouse striatal medium spiny neurons. J. Neurophysiol. 98, 2693–2704 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    Brothwell, S. L. et al. NR2B- and NR2D-containing synaptic NMDA receptors in developing rat substantia nigra pars compacta dopaminergic neurones. J. Physiol. 586, 739–750 (2008).

    CAS  PubMed  Google Scholar 

  33. 33

    Harney, S. C., Jane, D. E. & Anwyl, R. Extrasynaptic NR2D-containing NMDARs are recruited to the synapse during LTP of NMDAR-EPSCs. J. Neurosci. 28, 11685–11694 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Schwartz, E. J. et al. NMDA receptors with incomplete Mg2+ block enable low-frequency transmission through the cerebellar cortex. J. Neurosci. 32, 6878–6893 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Tovar, K. R. & Westbrook, G. L. Mobile NMDA receptors at hippocampal synapses. Neuron 34, 255–264 (2002). The first study to show that synaptic NMDARs can exchange rapidly between extrasynaptic and synaptic compartments through lateral membrane diffusion.

    CAS  PubMed  Google Scholar 

  36. 36

    Groc, L. et al. NMDA receptor surface mobility depends on NR2A-2B subunits. Proc. Natl Acad. Sci. USA 103, 18769–18774 (2006).

    CAS  PubMed  Google Scholar 

  37. 37

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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Mayer, M. L. Emerging models of glutamate receptor ion channel structure and function. Structure 19, 1370–1380 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Karakas, E., Simorowski, N. & Furukawa, H. Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature 475, 249–253 (2011). This study reports the X-ray crystal structure of a GluN1/GluN2B NTD heterodimer in a complex with the GluN2B-selective antagonist ifenprodil.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Furukawa, H., Singh, S. K., Mancusso, R. & Gouaux, E. Subunit arrangement and function in NMDA receptors. Nature 438, 185–192 (2005). The first X-ray crystal structure of a GluN1/GluN2 ABD heterodimer in a complex with glycine and glutamate.

    CAS  PubMed  Google Scholar 

  41. 41

    Salussolia, C. L., Prodromou, M. L., Borker, P. & Wollmuth, L. P. Arrangement of subunits in functional NMDA receptors. J. Neurosci. 31, 11295–11304 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Riou, M., Stroebel, D., Edwardson, J. M. & Paoletti, P. An alternating GluN1-2-1-2 subunit arrangement in mature NMDA receptors. PLoS ONE 7, e35134 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Sobolevsky, A. I., Rosconi, M. P. & Gouaux, E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462, 745–756 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Gielen, M. et al. Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition. Neuron 57, 80–93 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Gielen, M., Siegler Retchless, B., Mony, L., Johnson, J. W. & Paoletti, P. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459, 703–707 (2009). The study, together with reference 48, revealed that the large extracellular NTD of GluN2 subunits, which is the most distal domain from the membrane region, controls several key subunit-specific gating and pharmacological properties.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Siegler Retchless, B., Gao, W. & Johnson, J. W. A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction. Nature Neurosci. 15, 406–413 (2012). The authors show that three crucial NMDAR channel properties, Mg2+ blockade, Ca2+ permeability and single-channel conductance, are all controlled primarily by a single GluN2 residue in the M3 transmembrane region.

    PubMed  Google Scholar 

  47. 47

    Vicini, S. et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J. Neurophysiol. 79, 555–566 (1998).

    CAS  PubMed  Google Scholar 

  48. 48

    Yuan, H., Hansen, K. B., Vance, K. M., Ogden, K. K. & Traynelis, S. F. Control of NMDA receptor function by the NR2 subunit amino-terminal domain. J. Neurosci. 29, 12045–12058 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

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

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Banke, T. G., Dravid, S. M. & Traynelis, S. F. Protons trap NR1/NR2B NMDA receptors in a nonconducting state. J. Neurosci. 25, 42–51 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Mony, L., Zhu, S., Carvalho, S. & Paoletti, P. Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines. EMBO J. 30, 3134–3146 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Rachline, J., Perin-Dureau, F., Le Goff, A., Neyton, J. & Paoletti, P. The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. J. Neurosci. 25, 308–317 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

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

    CAS  PubMed  Google Scholar 

  54. 54

    Nozaki, C. et al. Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit. Nature Neurosci. 14, 1017–1022 (2011).

    CAS  PubMed  Google Scholar 

  55. 55

    Rodenas-Ruano, A., Chavez, A. E., Cossio, M. J., Castillo, P. E. & Zukin, R. S. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nature Neurosci. 15, 1382–1390 (2012). This study reveals a new role for the transcriptional repressor REST in the GluN2B-to-GluN2A subunit switch that occurs after birth.

    CAS  PubMed  Google Scholar 

  56. 56

    Papouin, T. et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150, 633–646 (2012).

    CAS  PubMed  Google Scholar 

  57. 57

    Hatton, C. J. & Paoletti, P. Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron 46, 261–274 (2005). In this study, the authors combine mutagenesis and pharmacological experiments to isolate tri-heteromeric GluN1/GluN2A/GluN2B and GluN1/GluN2A/GluN2C receptors and characterize their sensitivity to the subunit-specific allosteric inhibitors Zn2+ and ifenprodil.

    CAS  PubMed  Google Scholar 

  58. 58

    Bettini, E. et al. Identification and characterization of novel NMDA receptor antagonists selective for NR2A- over NR2B-containing receptors. J. Pharmacol. Exp. Ther. 335, 636–644 (2010).

    CAS  PubMed  Google Scholar 

  59. 59

    Hansen, K. B., Ogden, K. K. & Traynelis, S. F. Subunit-selective allosteric inhibition of glycine binding to NMDA receptors. J. Neurosci. 32, 6197–6208 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Hansen, K. B. & Traynelis, S. F. Structural and mechanistic determinants of a novel site for noncompetitive inhibition of GluN2D-containing NMDA receptors. J. Neurosci. 31, 3650–3661 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Mullasseril, P. et al. A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors. Nature Commun. 1, 90 (2010).

    Google Scholar 

  62. 62

    McKay, S. et al. Direct pharmacological monitoring of the developmental switch in NMDA receptor subunit composition using TCN 213, a GluN2A-selective, glycine-dependent antagonist. Br. J. Pharmacol. 166, 924–937 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Sprengel, R. et al. Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell 92, 279–289 (1998).

    CAS  PubMed  Google Scholar 

  64. 64

    Martel, M. A. et al. The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron 74, 543–556 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Sanz-Clemente, A., Nicoll, R. A. & Roche, K. W. Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist 19, 62–75 (2012).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Mu, Y., Otsuka, T., Horton, A. C., Scott, D. B. & Ehlers, M. D. Activity-dependent mRNA splicing controls ER export and synaptic delivery of NMDA receptors. Neuron 40, 581–594 (2003).

    CAS  PubMed  Google Scholar 

  67. 67

    Perez-Otano, I. et al. Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1. Nature Neurosci. 9, 611–621 (2006).

    CAS  PubMed  Google Scholar 

  68. 68

    Prybylowski, K. et al. The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron 47, 845–857 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Bard, L. et al. Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. Proc. Natl Acad. Sci. USA 107, 19561–19566 (2010).

    CAS  PubMed  Google Scholar 

  70. 70

    Sans, N. et al. A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J. Neurosci. 20, 1260–1271 (2000).

    CAS  PubMed  Google Scholar 

  71. 71

    Chung, H. J., Huang, Y. H., Lau, L. F. & Huganir, R. L. Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J. Neurosci. 24, 10248–10259 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Sanz-Clemente, A., Matta, J. A., Isaac, J. T. & Roche, K. W. Casein kinase 2 regulates the NR2 subunit composition of synaptic NMDA receptors. Neuron 67, 984–996 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

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

    CAS  Google Scholar 

  74. 74

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

    CAS  PubMed  Google Scholar 

  75. 75

    Lisman, J., Yasuda, R. & Raghavachari, S. Mechanisms of CaMKII action in long-term potentiation. Nature Rev. Neurosci. 13, 169–182 (2012).

    CAS  Google Scholar 

  76. 76

    Wang, C. C. et al. A critical role for GluN2B-containing NMDA receptors in cortical development and function. Neuron 72, 789–805 (2011).

    CAS  PubMed  Google Scholar 

  77. 77

    Gambrill, A. C. & Barria, A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc. Natl Acad. Sci. USA 108, 5855–5860 (2011).

    CAS  PubMed  Google Scholar 

  78. 78

    Krapivinsky, G. et al. The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 40, 775–784 (2003).

    CAS  PubMed  Google Scholar 

  79. 79

    Dumas, T. C. Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning. Prog. Neurobiol. 76, 189–211 (2005).

    CAS  PubMed  Google Scholar 

  80. 80

    Barth, A. L. & Malenka, R. C. NMDAR EPSC kinetics do not regulate the critical period for LTP at thalamocortical synapses. Nature Neurosci. 4, 235–236 (2001).

    CAS  PubMed  Google Scholar 

  81. 81

    Lavezzari, G., McCallum, J., Lee, R. & Roche, K. W. Differential binding of the AP-2 adaptor complex and PSD-95 to the C-terminus of the NMDA receptor subunit NR2B regulates surface expression. Neuropharmacology 45, 729–737 (2003).

    CAS  PubMed  Google Scholar 

  82. 82

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

    CAS  PubMed  Google Scholar 

  83. 83

    Bellone, C. & Nicoll, R. A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55, 779–785 (2007). This is the first study to describe a rapid (within seconds) switch in NMDAR subunit composition triggered by neuronal activity.

    CAS  PubMed  Google Scholar 

  84. 84

    Bellone, C., Mameli, M. & Luscher, C. In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA. Nature Neurosci. 14, 1439–1446 (2011).

    CAS  PubMed  Google Scholar 

  85. 85

    Matta, J. A., Ashby, M. C., Sanz-Clemente, A., Roche, K. W. & Isaac, J. T. mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch. Neuron 70, 339–351 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Philpot, B. D., Sekhar, A. K., Shouval, H. Z. & Bear, M. F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).

    CAS  PubMed  Google Scholar 

  88. 88

    Al-Hallaq, R. A. et al. Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. Mol. Pharmacol. 62, 1119–1127 (2002).

    CAS  PubMed  Google Scholar 

  89. 89

    Das, S. et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393, 377–381 (1998).

    CAS  PubMed  Google Scholar 

  90. 90

    Henson, M. A. et al. Genetic deletion of NR3A accelerates glutamatergic synapse maturation. PLoS ONE 7, e42327 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Roberts, A. C. et al. Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 63, 342–356 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Hunt, D. L. & Castillo, P. E. Synaptic plasticity of NMDA receptors: mechanisms and functional implications. Curr. Opin. Neurobiol. 22, 496–508 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Muller, D. & Lynch, G. Long-term potentiation differentially affects two components of synaptic responses in hippocampus. Proc. Natl Acad. Sci. USA 85, 9346–9350 (1988).

    CAS  PubMed  Google Scholar 

  94. 94

    Bashir, Z. I., Alford, S., Davies, S. N., Randall, A. D. & Collingridge, G. L. Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature 349, 156–158 (1991).

    CAS  PubMed  Google Scholar 

  95. 95

    Kauer, J. A., Malenka, R. C. & Nicoll, R. A. A persistent postsynaptic modification mediates long-term potentiation in the hippocampus. Neuron 1, 911–917 (1988).

    CAS  PubMed  Google Scholar 

  96. 96

    Peng, Y. et al. Distinct trafficking and expression mechanisms underlie LTP and LTD of NMDA receptor-mediated synaptic responses. Hippocampus 20, 646–658 (2010).

    CAS  PubMed  Google Scholar 

  97. 97

    Watt, A. J., Sjostrom, P. J., Hausser, M., Nelson, S. B. & Turrigiano, G. G. A proportional but slower NMDA potentiation follows AMPA potentiation in LTP. Nature Neurosci. 7, 518–524 (2004).

    CAS  PubMed  Google Scholar 

  98. 98

    Kwon, H. B. & Castillo, P. E. Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses. Neuron 57, 108–120 (2008). This study, together with reference 99, reveals a novel form of plasticity at hippocampal mossy fibre–CA3 synapses that involves a selective enhancement of NMDAR-mediated transmission.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Rebola, N., Lujan, R., Cunha, R. A. & Mulle, C. Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses. Neuron 57, 121–134 (2008).

    CAS  PubMed  Google Scholar 

  100. 100

    Harnett, M. T., Bernier, B. E., Ahn, K. C. & Morikawa, H. Burst-timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons. Neuron 62, 826–838 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Grosshans, D. R., Clayton, D. A., Coultrap, S. J. & Browning, M. D. LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1. Nature Neurosci. 5, 27–33 (2002).

    CAS  PubMed  Google Scholar 

  102. 102

    Skeberdis, V. A. et al. Protein kinase A regulates calcium permeability of NMDA receptors. Nature Neurosci. 9, 501–510 (2006).

    CAS  PubMed  Google Scholar 

  103. 103

    Sobczyk, A. & Svoboda, K. Activity-dependent plasticity of the NMDA-receptor fractional Ca2+ current. Neuron 53, 17–24 (2007).

    CAS  PubMed  Google Scholar 

  104. 104

    Chalifoux, J. R. & Carter, A. G. GABAB receptors modulate NMDA receptor calcium signals in dendritic spines. Neuron 66, 101–113 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Xiao, M. Y., Wigstrom, H. & Gustafsson, B. Long-term depression in the hippocampal CA1 region is associated with equal changes in AMPA and NMDA receptor-mediated synaptic potentials. Eur. J. Neurosci. 6, 1055–1057 (1994).

    CAS  PubMed  Google Scholar 

  106. 106

    Selig, D. K., Hjelmstad, G. O., Herron, C., Nicoll, R. A. & Malenka, R. C. Independent mechanisms for long-term depression of AMPA and NMDA responses. Neuron 15, 417–426 (1995).

    CAS  PubMed  Google Scholar 

  107. 107

    Montgomery, J. M., Selcher, J. C., Hanson, J. E. & Madison, D. V. Dynamin-dependent NMDAR endocytosis during LTD and its dependence on synaptic state. BMC Neurosci. 6, 48 (2005).

    PubMed  PubMed Central  Google Scholar 

  108. 108

    Morishita, W., Marie, H. & Malenka, R. C. Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nature Neurosci. 8, 1043–1050 (2005).

    CAS  PubMed  Google Scholar 

  109. 109

    Jo, J. et al. Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. Nature Neurosci. 13, 1216–1224 (2010).

    CAS  PubMed  Google Scholar 

  110. 110

    Ireland, D. R. & Abraham, W. C. Mechanisms of group I mGluR-dependent long-term depression of NMDA receptor-mediated transmission at Schaffer collateral–CA1 synapses. J. Neurophysiol. 101, 1375–1385 (2009).

    CAS  PubMed  Google Scholar 

  111. 111

    Berberich, S., Jensen, V., Hvalby, Ø., Seeburg, P. H. & Kohr, G. The role of NMDAR subtypes and charge transfer during hippocampal LTP induction. Neuropharmacology 52, 77–86 (2007).

    CAS  PubMed  Google Scholar 

  112. 112

    Sakimura, K. et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor ε1 subunit. Nature 373, 151–155 (1995).

    CAS  PubMed  Google Scholar 

  113. 113

    Zhao, J. P. & Constantine-Paton, M. NR2A−/− mice lack long-term potentiation but retain NMDA receptor and L-type Ca2+ channel-dependent long-term depression in the juvenile superior colliculus. J. Neurosci. 27, 13649–13654 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Andreescu, C. E. et al. NR2A subunit of the N-methyl D-aspartate receptors are required for potentiation at the mossy fiber to granule cell synapse and vestibulo-cerebellar motor learning. Neuroscience 176, 274–283 (2011).

    CAS  PubMed  Google Scholar 

  115. 115

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

    CAS  PubMed  Google Scholar 

  116. 116

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

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Dalton, G. L., Wu, D. C., Wang, Y. T., Floresco, S. B. & Phillips, A. G. NMDA GluN2A and GluN2B receptors play separate roles in the induction of LTP and LTD in the amygdala and in the acquisition and extinction of conditioned fear. Neuropharmacology 62, 797–806 (2012).

    CAS  PubMed  Google Scholar 

  118. 118

    Brigman, J. L. et al. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J. Neurosci. 30, 4590–4600 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Tang, Y. P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    CAS  PubMed  Google Scholar 

  120. 120

    Clayton, D. A., Mesches, M. H., Alvarez, E., Bickford, P. C. & Browning, M. D. A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J. Neurosci. 22, 3628–3637 (2002).

    CAS  PubMed  Google Scholar 

  121. 121

    Berberich, S. et al. Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. J. Neurosci. 25, 6907–6910 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Weitlauf, C. et al. Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation. J. Neurosci. 25, 8386–8390 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Bartlett, T. E. et al. Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology 52, 60–70 (2007).

    CAS  PubMed  Google Scholar 

  124. 124

    Morishita, W. et al. Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression. Neuropharmacology 52, 71–76 (2007).

    CAS  PubMed  Google Scholar 

  125. 125

    Miwa, H., Fukaya, M., Watabe, A. M., Watanabe, M. & Manabe, T. Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS. J. Physiol. 586, 2539–2550 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    von Engelhardt, J. et al. Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60, 846–860 (2008).

    CAS  PubMed  Google Scholar 

  127. 127

    Müller, T., Albrecht, D. & Gebhardt, C. 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 (2009).

    PubMed  Google Scholar 

  128. 128

    Gardoni, F. et al. Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression. J. Neurosci. 29, 669–677 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Wang, D. et al. Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats. PLoS ONE 4, e7486 (2009).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    Neyton, J. & Paoletti, P. Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. J. Neurosci. 26, 1331–1333 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Frizelle, P. A., Chen, P. E. & Wyllie, D. J. Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: implications for studies of synaptic transmission. Mol. Pharmacol. 70, 1022–1032 (2006).

    CAS  PubMed  Google Scholar 

  132. 132

    Foster, K. A. et al. Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. J. Neurosci. 30, 2676–2685 (2010). An interesting study that reconciles a highly controversial field by proposing that at mature synapses both, GluN2A and GluN2B subunits cooperate to induce LTP — GluN2A as part of the conducting channel and GluN2B as a structural scaffold for recruiting proteins that are important for LTP.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Delaney, A. J., Sedlak, P. L., Autuori, E., Power, J. M. & Sah, P. Synaptic NMDA receptors in basolateral amygdala principal neurons are triheteromeric proteins: physiological role of GluN2B subunits. J. Neurophysiol. 109, 1319–1402 (2012).

    Google Scholar 

  134. 134

    Halt, A. R. et al. CaMKII binding to GluN2B is critical during memory consolidation. EMBO J. 31, 1203–1216 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Rebola, N., Carta, M., Lanore, F., Blanchet, C. & Mulle, C. NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses. Nature Neurosci. 14, 691–693 (2011).

    CAS  PubMed  Google Scholar 

  136. 136

    Xu, Z. et al. Metaplastic regulation of long-term potentiation/long-term depression threshold by activity-dependent changes of NR2A/NR2B ratio. J. Neurosci. 29, 8764–8773 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Philpot, B. D., Cho, K. K. & Bear, M. F. Obligatory role of NR2A for metaplasticity in visual cortex. Neuron 53, 495–502 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Lee, M. C., Yasuda, R. & Ehlers, M. D. Metaplasticity at single glutamatergic synapses. Neuron 66, 859–870 (2010). In this study, by manipulating local synaptic activity, the authors demonstrate that prior activity determines the propensity for plasticity by regulating the GluN2B subunit content at single synapses.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Kopp, C., Longordo, F., Nicholson, J. R. & Luthi, A. Insufficient sleep reversibly alters bidirectional synaptic plasticity and NMDA receptor function. J. Neurosci. 26, 12456–12465 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Yang, K. et al. Metaplasticity gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases. EMBO J. 31, 805–816 (2012).

    CAS  PubMed  Google Scholar 

  141. 141

    Endele, S. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature Genet. 42, 1021–1026 (2010).

    CAS  PubMed  Google Scholar 

  142. 142

    Lai, T. W., Shyu, W. C. & Wang, Y. T. Stroke intervention pathways: NMDA receptors and beyond. Trends Mol. Med. 17, 266–275 (2011).

    CAS  PubMed  Google Scholar 

  143. 143

    Aarts, M. et al. Treatment of ischemic brain damage by perturbing NMDA receptor–PSD-95 protein interactions. Science 298, 846–850 (2002). This is the first paper to demonstrate that disrupting the interaction between GluN2B NMDARs and PSD95 reduces neuronal damage during ischaemia and improves neurological functions.

    CAS  PubMed  Google Scholar 

  144. 144

    Tu, W. et al. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140, 222–234 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Cook, D. J., Teves, L. & Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217 (2012).

    CAS  PubMed  Google Scholar 

  146. 146

    Hill, M. D. et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 11, 942–950 (2012).

    CAS  PubMed  Google Scholar 

  147. 147

    Jullienne, A. et al. Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo. Mol. Neurodegener. 6, 68 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    von Engelhardt, J. et al. Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors. Neuropharmacology 53, 10–17 (2007).

    CAS  PubMed  Google Scholar 

  149. 149

    Liu, Y. et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27, 2846–2857 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Chen, M. et al. Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 39, 3042–3048 (2008).

    CAS  PubMed  Google Scholar 

  151. 151

    Terasaki, Y. et al. Activation of NR2A receptors induces ischemic tolerance through CREB signaling. J. Cereb. Blood Flow Metab. 30, 1441–1449 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Parsons, C. G., Stoffler, A. & Danysz, W. 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 (2007).

    CAS  PubMed  Google Scholar 

  153. 153

    Xia, P., Chen, H. S., Zhang, D. & Lipton, S. A. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J. Neurosci. 30, 11246–11250 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Kotermanski, S. E. & Johnson, J. W. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J. Neurosci. 29, 2774–2779 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci. 8, 1051–1058 (2005).

    CAS  PubMed  Google Scholar 

  156. 156

    Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Ronicke, R. et al. Early neuronal dysfunction by amyloid β oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiol. Aging 32, 2219–2228 (2011).

    PubMed  Google Scholar 

  158. 158

    Li, S. et al. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31, 6627–6638 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Hu, N. W., Klyubin, I., Anwyl, R. & Rowan, M. J. GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo. Proc. Natl Acad. Sci. USA 106, 20504–20509 (2009).

    CAS  PubMed  Google Scholar 

  160. 160

    Li, S. et al. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

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

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Ittner, L. M. et al. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer's disease mouse models. Cell 142, 387–397 (2010). This paper shows that dendritic tau mediates the toxicity of A β by targeting receptor protein kinase FYN to postsynaptic locations. This in turn mediates the interaction between NMDARs and PSD95, which causes excitotoxicity.

    CAS  PubMed  Google Scholar 

  163. 163

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

    CAS  PubMed  Google Scholar 

  164. 164

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

    CAS  PubMed  Google Scholar 

  165. 165

    Sgambato-Faure, V. & Cenci, M. A. Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease. Prog. Neurobiol. 96, 69–86 (2012).

    CAS  PubMed  Google Scholar 

  166. 166

    Hallett, P. J. et al. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Neuropharmacology 48, 503–516 (2005).

    CAS  PubMed  Google Scholar 

  167. 167

    Gardoni, F. et al. A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. J. Neurosci. 26, 2914–2922 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Gardoni, F. et al. Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias. Neurobiol. Aging 33, 2138–2144 (2012).

    CAS  PubMed  Google Scholar 

  169. 169

    Magnusson, K. R., Brim, B. L. & Das, S. R. Selective vulnerabilities of N-methyl-D-aspartate (NMDA) receptors during brain aging. Front. Aging Neurosci. 2, 11 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Cao, X. et al. Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur. J. Neurosci. 25, 1815–1822 (2007).

    PubMed  Google Scholar 

  171. 171

    Moghaddam, B. & Javitt, D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37, 4–15 (2012).

    CAS  PubMed  Google Scholar 

  172. 172

    Mohn, A. R., Gainetdinov, R. R., Caron, M. G. & Koller, B. H. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98, 427–436 (1999).

    CAS  PubMed  Google Scholar 

  173. 173

    Belforte, J. E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neurosci. 13, 76–83 (2010). In this work, the authors show that deletion of NMDARs from a subset of corticolimbic GABAergic interneurons in mice is sufficient to cause various schizophrenia-like behavioural phenotypes. Interestingly, these phenotypes are seen when NMDARs are deleted during postnatal development but not in adulthood.

    CAS  PubMed  Google Scholar 

  174. 174

    Kinney, J. W. et al. A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J. Neurosci. 26, 1604–1615 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Woo, T. U., Walsh, J. P. & Benes, F. M. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch. Gen. Psychiatry 61, 649–657 (2004).

    CAS  PubMed  Google Scholar 

  176. 176

    Mueller, H. T. & Meador-Woodruff, J. H. NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. Schizophr. Res. 71, 361–370 (2004).

    PubMed  Google Scholar 

  177. 177

    Jacobs, S. A. & Tsien, J. Z. genetic overexpression of NR2B subunit enhances social recognition memory for different strains and species. PLoS ONE 7, e36387 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Boyce-Rustay, J. M. & Holmes, A. Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic- and antidepressant-like effects in mice. Neuropsychopharmacology 31, 2405–2414 (2006).

    CAS  PubMed  Google Scholar 

  179. 179

    Bannerman, D. M. et al. NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory. J. Neurosci. 28, 3623–3630 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Corlew, R., Brasier, D. J., Feldman, D. E. & Philpot, B. D. Presynaptic NMDA receptors: newly appreciated roles in cortical synaptic function and plasticity. Neuroscientist 14, 609–625 (2008).

    PubMed  PubMed Central  Google Scholar 

  181. 181

    Woodhall, G., Evans, D. I., Cunningham, M. O. & Jones, R. S. NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons. J. Neurophysiol. 86, 1644–1651 (2001).

    CAS  PubMed  Google Scholar 

  182. 182

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

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

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

    CAS  PubMed  Google Scholar 

  184. 184

    Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nature Neurosci. 10, 331–339 (2007).

    CAS  PubMed  Google Scholar 

  185. 185

    Larsen, R. S. et al. NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nature Neurosci. 14, 338–344 (2011).

    CAS  PubMed  Google Scholar 

  186. 186

    Christie, J. M. & Jahr, C. E. Selective expression of ligand-gated ion channels in L5 pyramidal cell axons. J. Neurosci. 29, 11441–11450 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Buchanan, K. A. et al. Target-specific expression of presynaptic NMDA receptors in neocortical microcircuits. Neuron 75, 451–466 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 188

    Wu, L. J. & Zhuo, M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics 6, 693–702 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Matsumura, S. et al. Impairment of CaMKII activation and attenuation of neuropathic pain in mice lacking NR2B phosphorylated at Tyr1472. Eur. J. Neurosci. 32, 798–810 (2010).

    PubMed  Google Scholar 

  190. 190

    Petrenko, A. B., Yamakura, T., Baba, H. & Shimoji, K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth. Analg. 97, 1108–1116 (2003).

    CAS  PubMed  Google Scholar 

  191. 191

    Heng, M. Y., Detloff, P. J., Wang, P. L., Tsien, J. Z. & Albin, R. L. In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J. Neurosci. 29, 3200–3205 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Milnerwood, A. J. et al. Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron 65, 178–190 (2010)..

    CAS  PubMed  Google Scholar 

  193. 193

    Zarate, C. A. Jr. et al. A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am. J. Psychiatry 163, 153–155 (2006).

    PubMed  Google Scholar 

  194. 194

    Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010). In an effort to identify the cellular substrate underlying the rapid antidepressant effects of ketamine and GluN2B-selective antagonists, this work demonstrates that activation of the mammalian target of rapamycin (mTOR) pathway and the subsequent increase in new synapses are likely to be relevant events.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Won, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 2012).

    CAS  PubMed  Google Scholar 

  197. 197

    Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012).

    CAS  PubMed  Google Scholar 

  198. 198

    Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008). Anti-NMDAR encephalitis is a newly discovered auto-immune disease in which patients display severe neurological and psychiatric symptoms associated with high titres of auto-antibodies targeting NMDARs. In this study, the authors show that the main epitope targeted by the patient's auto-antibodies is the GluN1 NTD, and that the main effect of the antibodies is to decrease the surface density of NMDARs.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Hughes, E. G. et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J. Neurosci. 30, 5866–5875 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200

    Mikasova, L. et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 135, 1606–1621 (2012).

    PubMed  Google Scholar 

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Acknowledgements

We thank S. Zhu for help with the figures and A. Vergnano for suggestions. We gratefully acknowledge the support of the Agence Nationale pour la Recherche (ANR), the Fondation pour la Recherche Médicale (FRM) and the Swiss National Science Foundation (SNSF).

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Correspondence to Pierre Paoletti.

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Glossary

Isoforms

Different versions of a given receptor subunit. The term usually refers to different splice forms.

Tri-heteromeric receptors

A class of NMDA receptors that contains three distinct subunits in the tetrameric receptor complex (for example, GluN1/GluN2A/GluN2B receptors).

CA3–CA1 synapses

Excitatory synapses in the hippocampus formed between axons (Schaffer collaterals) of CA3 pyramidal cells and dendrites of CA1 pyramidal cells. NMDA receptor-mediated plasticity (long-term potentiation and long-term depression) has been extensively studied at these synapses.

Allosteric regulation

A form of receptor modulation that involves domains or ligand-binding sites that are distinct from those to which the agonist binds.

Single-channel conductance

The single-channel current divided by the electrical driving force. It refers to the number of charges flowing through a single open channel under a given transmembrane potential and is usually expressed in picoSiemens (10−12 S).

Deactivation kinetics

The time course of the current decrease following agonist removal.

Excitatory postsynaptic cuurent (EPSC) decay

The decay time course of the EPSC. EPSC decay is a key parameter in the control of synaptic integration.

Long-term potentiation

A long-lasting (>1 h) and activity-dependent strengthening of synaptic transmission. It is widely considered to be a major cellular substrate for several forms of learning and memory.

Postsynaptic density

A protein-dense specialization that is attached to the postsynaptic membrane of excitatory synapses. It contains hundreds of proteins, including glutamate receptors, scaffold proteins and signalling molecules.

Critical period

A finite temporal window following birth during which neuronal circuits are shaped; it is characterized by heightened plasticity and experience-dependent remodelling.

Metaplasticity

A term that refers to the phenomenon whereby previous synaptic activity influences the occurrence of subsequent synaptic plasticity. It is commonly regarded as a mechanism to adjust synaptic plasticity according to the history of the synapse.

Synaptopathies

A term used to define disorders caused by disruption in synaptic structure and function. Synaptopathy is increasingly seen as a key feature of neurodegenerative and psychiatric diseases.

Excitotoxicity

Cell death induced by excessive extracellular glutamate concentrations.

Negative symptoms

A set of symptoms seen in patients with schizophrenia, including social withdrawal, loss of motivation and reduced affect.

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Paoletti, P., Bellone, C. & Zhou, Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14, 383–400 (2013). https://doi.org/10.1038/nrn3504

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