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NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

Key Points

  • Synaptic NMDARs (N-methyl-D-aspartate receptors) and AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), two major classes of glutamate-gated ion channels, are localized to postsynaptic densities (PSDs) where they are structurally organized (and spatially restricted) in a large macromolecular signalling complex of scaffolding and adaptor proteins, which physically links the receptors to kinases, phosphatases and other downstream signalling proteins.

  • NMDARs are synthesized and co-translationally assemble in the endoplasmic reticulum (ER) to form functional channels with differing physiological and pharmacological properties and distinct patterns of synaptic targeting. Nascent NMDARs are transported in vesicles with adaptor and scaffolding proteins by the kinesin motor KIF17 along microtubules in dendrites to synaptic sites.

  • New research provides evidence that synaptic NMDAR number and subunit composition are not static, but change dynamically in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting of receptors into the endosomal–lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites.

  • Homeostatic mechanisms limit NMDAR synaptic strength by regulating receptor number and phenotype at synaptic sites. Whereas activity blockade promotes alternative RNA splicing of the NR1 subunit and accelerates forward trafficking of NMDARs, chronic neuronal activity drives subunit-specific receptor internalization, intracellular sorting and protein degradation via the ubiquitin–proteasome system.

  • Emerging evidence indicates that activity-dependent insertion and retrieval of NMDARs to and from synaptic sites mediates some forms of long-term potentiation (LTP) and long-term depression (LTD), cellular processes that are widely believed to be involved in learning and memory, as well as metaplasticity at central synapses.

  • Dysregulation of NMDAR trafficking may have a role in the behavioural symptoms associated with neuropsychiatric disorders such as cocaine addiction, chronic alcohol abuse, schizophrenia and Alzheimer's disease.

Abstract

The number and subunit composition of synaptic N-methyl-D-aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal–lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.

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Figure 1: The NMDAR macromolecular signalling complex at excitatory synapses.
Figure 2: NMDAR assembly and transport to dendritic spines.
Figure 3: Synaptic activity regulates the molecular composition of the postsynaptic density.
Figure 4: NMDAR subunit targeting signals.
Figure 5: Long-term potentiation and long-term depression involve activity-dependent insertion or internalization of NMDARs.
Figure 6: Dysregulation of NMDAR trafficking in neuropsychiatric disorders.

References

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

    Article  PubMed  Google Scholar 

  2. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S. F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

    CAS  PubMed  Google Scholar 

  3. Carroll, R. C. & Zukin, R. S. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Neurosci. 25, 571–577 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Zukin, R. S. & Bennett, M. V. L. Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci. 18, 306–313 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Collingridge, G. L., Isaac, J. T. & Wang, Y. T. Receptor trafficking and synaptic plasticity. Nature Rev. Neurosci. 5, 952–962 (2004).

    Article  CAS  Google Scholar 

  6. Conn, P. J. & Pin, J. P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nature Rev. Neurosci. 5, 771–781 (2004).

    Article  CAS  Google Scholar 

  8. O'Brien, R. J. et al. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067–1078 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Friedman, H. V., Bresler, T., Garner, C. C. & Ziv, N. E. Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron 27, 57–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Washbourne, P., Bennett, J. E. & McAllister, A. K. Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nature Neurosci. 5, 751–759 (2002). The first study to use time-lapse fluorescence imaging of live cells to visualize packets of NMDARs transported from the cell body along dendrites to dendritic spines before and during synaptogenesis.

    Article  CAS  PubMed  Google Scholar 

  11. Washbourne, P., Liu, X. B., Jones, E. G. & McAllister, A. K. Cycling of NMDA receptors during trafficking in neurons before synapse formation. J. Neurosci. 24, 8253–8264 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bresler, T. et al. Postsynaptic density assembly is fundamentally different from presynaptic active zone assembly. J. Neurosci. 24, 1507–1520 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hirokawa, N. & Takemura, R. Molecular motors and mechanisms of directional transport in neurons. Nature Rev. Neurosci. 6, 201–214 (2005).

    Article  CAS  Google Scholar 

  14. Setou, M., Nakagawa, T., Seog, D. H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796–1802 (2000). Identified KIF17, a member of the kinesin family, as a motor involved in the transport of vesicles carrying newly synthesized NMDARs along microtubules.

    Article  CAS  PubMed  Google Scholar 

  15. Guillaud, L., Setou, M. & Hirokawa, N. KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons. J. Neurosci 23, 131–140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wong, R. W., Setou, M., Teng, J., Takei, Y. & Hirokawa, N. Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc. Natl Acad. Sci. USA 99, 14500–14505 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tovar, K. R. & Westbrook, G. L. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J. Neurosci. 19, 4180–4188 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Williams, K., Russell, S. L., Shen, Y. M. & Molinoff, P. B. Developmental switch in the expression of NMDA receptors occurs in vivo and in vitro. Neuron 10, 267–278 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Flint, A. C., Maisch, U. S., Weishaupt, J. H., Kriegstein, A. R. & Monyer, H. NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J. Neurosci. 17, 2469–2476 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. El Husseini, A. E., Schnell, E., Chetkovich, D. M., Nicoll, R. A. & Bredt, D. S. PSD-95 involvement in maturation of excitatory synapses. Science 290, 1364–1368 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Lavezzari, G., McCallum, J., Dewey, C. M. & Roche, K. W. Subunit-specific regulation of NMDA receptor endocytosis. J. Neurosci. 24, 6383–6391 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lin, Y., Skeberdis, V. A., Francesconi, A., Bennett, M. V. L. & Zukin, R. S. Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J. Neurosci. 24, 10138–10148 (2004). The first demonstration that a synaptic scaffolding protein regulates NMDA channel opening and surface expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Roche, K. W. et al. Molecular determinants of NMDA receptor internalization. Nature Neurosci. 4, 794–802 (2001). The first report of a trafficking signal in an NMDAR subunit. The paper identified a tyrosine-based internalization motif, YEKL, within the carboxyl terminus of the NR2B subunit and showed that binding of the synaptic scaffolding protein PSD-95 to a nearby PDZ-binding motif inhibited NMDAR internalization, stabilizing receptors at the cell surface.

    Article  CAS  PubMed  Google Scholar 

  27. Losi, G. et al. PSD-95 regulates NMDA receptors in developing cerebellar granule neurons of the rat. J. Physiol. 548, 21–29 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mori, H. et al. Role of the carboxy-terminal region of the GluR epsilon2 subunit in synaptic localization of the NMDA receptor channel. Neuron 21, 571–580 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Steigerwald, F. et al. C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors. J. Neurosci. 20, 4573–4581 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sattler, R. et al. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284, 1845–1848 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Li, B., Otsu, Y., Murphy, T. H. & Raymond, L. A. Developmental decrease in NMDA receptor desensitization associated with shift to synapse and interaction with postsynaptic density-95. J. Neurosci. 23, 11244–11254 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tao, Y. X. et al. Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein. J. Neurosci. 23, 6703–6712 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Elias, G. M. et al. Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 52, 307–320 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Ehlers, M. D. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nature Neurosci. 6, 231–242 (2003). The first demonstration that synaptic activity dictates long-lasting, global changes in the molecular composition of the PSD and that remodelling of the PSD occurs via activity-dependent protein degradation of a subset of synaptic proteins.

    Article  CAS  PubMed  Google Scholar 

  36. Scott, D. B., Blanpied, T. A., Swanson, G. T., Zhang, C. & Ehlers, M. D. An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J. Neurosci. 21, 3063–3072 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Standley, S., Roche, K. W., McCallum, J., Sans, N. & Wenthold, R. J. PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28, 887–898 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. Scott, D. B., Michailidis, I., Mu, Y., Logothetis, D. & Ehlers, M. D. Endocytosis and degradative sorting of NMDA receptors by conserved membrane-proximal signals. J. Neurosci. 24, 7096–7109 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hawkins, L. M. et al. Export from the endoplasmic reticulum of assembled N-methyl-D-aspartic acid receptors is controlled by a motif in the c terminus of the NR2 subunit. J. Biol. Chem. 279, 28903–28910 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Yang, W. et al. A three amino acid tail following the TM4 region of NR2 subunits is sufficient to overcome ER retention of NR1–1a subunit. J. Biol. Chem. 28, 9269–9278 (2007).

    Article  CAS  Google Scholar 

  42. McIlhinney, R. A. et al. Assembly intracellular targeting and cell surface expression of the human N-methyl-D-aspartate receptor subunits NR1a and NR2A in transfected cells. Neuropharmacology 37, 1355–1367 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Hall, R. A. & Soderling, T. R. Differential surface expression and phosphorylation of the N-methyl-D-aspartate receptor subunits NR1 and NR2 in cultured hippocampal neurons. J. Biol. Chem. 272, 4135–4140 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Sans, N. et al. NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex. Nature Cell Biol. 5, 520–530 (2003). The first demonstration of a physical interaction between an NMDAR subunit NR2B and a protein component of the exocyst complex, SEC8, and the role of SEC8 in promoting receptor delivery to the cell surface.

    Article  CAS  PubMed  Google Scholar 

  45. Sans, N. et al. mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nature Cell Biol. 7, 1179–1190 (2005).

    Article  PubMed  CAS  Google Scholar 

  46. Scott, D. B., Blanpied, T. A. & Ehlers, M. D. Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors. Neuropharmacology 45, 755–767 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Lan, J. Y. et al. Protein kinase C modulates NMDA receptor trafficking and gating. Nature Neurosci. 4, 382–390 (2001). The first demonstration of regulated NMDAR trafficking in neurons. This study used a combination of electrophysiological, molecular and imaging approaches to show that PKC potentiates NMDA channel opening and delivers new NMDA channels to the cell surface via SNARE-dependent exocytosis.

    Article  CAS  PubMed  Google Scholar 

  48. Zheng, X., Zhang, L., Wang, A. P., Bennett, M. V. L. & Zukin, R. S. Protein kinase C potentiation of N-methyl-D-aspartate receptor activity is not mediated by phosphorylation of N-methyl-D-aspartate receptor subunits. Proc. Natl Acad. Sci. USA 96, 15262–15267 (1999). The first evidence that NMDARs comprising mutant NR1 and NR2A subunits lacking all known sites of PKC phosphorylation exhibit PKC potentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lin, Y., Jover-Mengual, T., Wong, J., Bennett, M. V. L. & Zukin, R. S. PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating. Proc. Natl Acad. Sci. USA 103, 19902–19907 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rao, A. & Craig, A. M. Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19, 801–812 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Fong, D. K., Rao, A., Crump, F. T. & Craig, A. M. Rapid synaptic remodeling by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II. J. Neurosci. 22, 2153–2164 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lan, J. Y. et al. Activation of metabotropic glutamate receptor 1 accelerates NMDA receptor trafficking. J. Neurosci. 21, 6058–6068 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Skeberdis, V. A., Lan, J., Zheng, X., Zukin, R. S. & Bennett, M. V. Insulin promotes rapid delivery of N-methyl-D-aspartate receptors to the cell surface by exocytosis. Proc. Natl Acad. Sci. USA 98, 3561–3566 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schilstrom, B. et al. Cocaine enhances NMDA receptor-mediated currents in ventral tegmental area cells via dopamine D5 receptor-dependent redistribution of NMDA receptors. J. Neurosci. 26, 8549–8558 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hallett, P. J., Spoelgen, R., Hyman, B. T., Standaert, D. G. & Dunah, A. W. Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J. Neurosci. 26, 4690–4700 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dunah, A. W. & Standaert, D. G. Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane. J. Neurosci. 21, 5546–5558 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Blanpied, T. A., Scott, D. B. & Ehlers, M. D. Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron 36, 435–449 (2002). The first paper to report the presence of specialized endocytic zones localized tangential to the PSD. The study identified clathrin, AP2 and dynamin to be protein components of the endocytic zones, consistent with a role in synaptic receptor internalization.

    Article  CAS  PubMed  Google Scholar 

  58. Racz, B., Blanpied, T. A., Ehlers, M. D. & Weinberg, R. J. Lateral organization of endocytic machinery in dendritic spines. Nature Neurosci. 7, 917–918 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Choquet, D. & Triller, A. The role of receptor diffusion in the organization of the postsynaptic membrane. Nature Rev. Neurosci. 4, 251–265 (2003).

    Article  CAS  Google Scholar 

  60. Yaka, R. et al. NMDA receptor function is regulated by the inhibitory scaffolding protein, RACK1. Proc. Natl Acad. Sci. USA 99, 5710–5715 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nakazawa, T. et al. NR2B tyrosine phosphorylation modulates fear learning as well as amygdaloid synaptic plasticity. EMBO J. 25, 2867–2877 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vissel, B., Krupp, J. J., Heinemann, S. F. & Westbrook, G. L. A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux. Nature Neurosci. 4, 587–596 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Li, B. et al. Differential regulation of synaptic and extra-synaptic NMDA receptors. Nature Neurosci. 5, 833–834 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Nong, Y. et al. Glycine binding primes NMDA receptor internalization. Nature 422, 302–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Malenka, R. C. & Nicoll, R. A. Long-term potentiation-a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Benke, T. A., Jones, O. T., Collingridge, G. L. & Angelides, K. J. N-Methyl-D-aspartate receptors are clustered and immobilized on dendrites of living cortical neurons. Proc. Natl Acad. Sci. USA 90, 7819–7823 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tovar, K. R. & Westbrook, G. L. Mobile NMDA receptors at hippocampal synapses. Neuron 34, 255–264 (2002). The first report that NMDARs can move laterally within the plasma membrane between synaptic and extrasynaptic sites. The study used single-molecule tracking and time-lapse live imaging of neurons to measure the rate of mobility of synaptic NMDARs.

    Article  CAS  PubMed  Google Scholar 

  68. Groc, L. et al. Differential activity-dependent regulation of the lateral mobilities of AMPA and NMDA receptors. Nature Neurosci. 7, 695–696 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Derkach, V. A., Oh, M. C., Guire, E. S. & Soderling, T. R. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nature Rev. Neurosci. 8, 101–113 (2007).

    Article  CAS  Google Scholar 

  71. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Liu, S. Q. & Zukin, R. S. Calcium permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci. 30, 126–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Berretta, N. et al. Long-term potentiation of NMDA receptor-mediated EPSP in guinea-pig hippocampal slices. Eur. J. Neurosci. 3, 850–854 (1991).

    Article  PubMed  Google Scholar 

  74. Asztely, F., Wigstrom, H. & Gustafsson, B. The relative contribution of NMDA receptor channels in the expression of long-term potentiation in the hippocampal CA1 region. Eur. J. Neurosci. 4, 681–690 (1992).

    Article  PubMed  Google Scholar 

  75. 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). The first report of LTP of isolated NMDA EPSCs in the hippocampus.

    Article  CAS  PubMed  Google Scholar 

  76. O'Connor, J. J., Rowan, M. J. & Anwyl, R. Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation. Nature 367, 557–559 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Harney, S. C., Rowan, M. & Anwyl, R. Long-term depression of NMDA receptor-mediated synaptic transmission is dependent on activation of metabotropic glutamate receptors and is altered to long-term potentiation by low intracellular calcium buffering. J. Neurosci. 26, 1128–1132 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 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). The first demonstration that the rapid insertion of new NMDA channels at synaptic sites underlies the expression of NMDAR-dependent LTP at central synapses and is regulated in a PKC- and Src-dependent manner.

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Jia, Z. et al. Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learn. Mem. 5, 331–343 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lu, W. Y. et al. G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nature Neurosci. 2, 331–338 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Kotecha, S. A. et al. Co-stimulation of mGluR5 and N-methyl-D-aspartate receptors is required for potentiation of excitatory synaptic transmission in hippocampal neurons. J. Biol. Chem. 278, 27742–27749 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Smith, C. C. & McMahon, L. L. Estradiol-induced increase in the magnitude of long-term potentiation is prevented by blocking NR2B-containing receptors. J. Neurosci. 26, 8517–8522 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Smith, C. C. & McMahon, L. L. Estrogen-induced increase in the magnitude of long-term potentiation occurs only when the ratio of NMDA transmission to AMPA transmission is increased. J. Neurosci. 25, 7780–7791 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Carroll, R. C., Beattie, E. C., von Zastrow, M. & Malenka, R. C. Role of AMPA receptor endocytosis in synaptic plasticity. Nature Rev. Neurosci. 2, 315–324 (2001).

    Article  CAS  Google Scholar 

  86. Lisman, J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl Acad. Sci. USA 86, 9574–9578 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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). Together with reference 88, this is the first demonstration that AMPARs and NMDARs express LTD through distinct signal transduction mechanisms.

    Article  CAS  PubMed  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. Zhang, S., Ehlers, M. D., Bernhardt, J. P., Su, C. T. & Huganir, R. L. Calmodulin mediates calcium-dependent inactivation of N-methyl-D-aspartate receptors. Neuron 21, 443–453 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Krupp, J. J., Vissel, B., Thomas, C. G., Heinemann, S. F. & Westbrook, G. L. Interactions of calmodulin and α-actinin with the NR1 subunit modulate Ca2+-dependent inactivation of NMDA receptors. J. Neurosci. 19, 1165–1178 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Montgomery, J. M. & Madison, D. V. State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron 33, 765–777 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Snyder, E. M. et al. Internalization of ionotropic glutamate receptors in response to mGluR activation. Nature Neurosci. 4, 1079–1085 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Aniksztejn, L. & Ben-Ari, Y. Expression of LTP by AMPA and/or NMDA receptors is determined by the extent of NMDA receptors activation during the tetanus. J. Neurophysiol. 74, 2349–2357 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Bayazitov, I. & Kleschevnikov, A. Afferent high strength tetanizations favour potentiation of the NMDA vs. AMPA receptor-mediated component of field EPSP in CA1 hippocampal slices of rats. Brain Res. 866, 188–196 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Hensch, T. K. Critical period plasticity in local cortical circuits. Nature Rev. Neurosci. 6, 877–888 (2005).

    Article  CAS  Google Scholar 

  97. Karmarkar, U. R. & Dan, Y. Experience-dependent plasticity in adult visual cortex. Neuron 52, 577–585 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992).

    Article  CAS  PubMed  Google Scholar 

  99. Quinlan, E. M., Philpot, B. D., Huganir, R. L. & Bear, M. F. Rapid, experience-dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nature Neurosci. 2, 352–357 (1999). The first demonstration that visual experience can rapidly — within hours — alter the number and phenotype of synaptic NMDARs in the visual cortex.

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  CAS  PubMed  Google Scholar 

  101. Quinlan, E. M., Olstein, D. H. & Bear, M. F. Bidirectional, experience-dependent regulation of N-methyl-D-aspartate receptor subunit composition in the rat visual cortex during postnatal development. Proc. Natl Acad. Sci. USA 96, 12876–12880 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Philpot, B. D., Espinosa, J. S. & Bear, M. F. Evidence for altered NMDA receptor function as a basis for metaplasticity in visual cortex. J. Neurosci. 23, 5583–5588 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Abraham, W. C. & Bear, M. F. Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Kirkwood, A., Lee, H. K. & Bear, M. F. Co-regulation of long-term potentiation and experience-dependent synaptic plasticity in visual cortex by age and experience. Nature 375, 328–331 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lu, H. C., Gonzalez, E. & Crair, M. C. Barrel cortex critical period plasticity is independent of changes in NMDA receptor subunit composition. Neuron 32, 619–634 (2001).

    Article  PubMed  Google Scholar 

  109. 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).

    Article  CAS  PubMed  Google Scholar 

  110. Fagiolini, M. et al. Separable features of visual cortical plasticity revealed by N-methyl-D-aspartate receptor 2A signaling. Proc. Natl Acad. Sci. USA 100, 2854–2859 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Quinlan, E. M., Lebel, D., Brosh, I. & Barkai, E. A molecular mechanism for stabilization of learning-induced synaptic modifications. Neuron 41, 185–192 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Franks, K. M. & Isaacson, J. S. Synapse-specific downregulation of NMDA receptors by early experience: a critical period for plasticity of sensory input to olfactory cortex. Neuron 47, 101–114 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Mierau, S. B., Meredith, R. M., Upton, A. L. & Paulsen, O. Dissociation of experience-dependent and-independent changes in excitatory synaptic transmission during development of barrel cortex. Proc. Natl Acad. Sci. USA 101, 15518–15523 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Takahashi, T., Svoboda, K. & Malinow, R. Experience strengthening transmission by driving AMPA receptors into synapses. Science 299, 1585–1588 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Turrigiano, G. G. & Nelson, S. B. Homeostatic plasticity in the developing nervous system. Nature Rev. Neurosci. 5, 97–107 (2004).

    Article  CAS  Google Scholar 

  116. Watt, A. J., van Rossum, M. C., MacLeod, K. M., Nelson, S. B. & Turrigiano, G. G. Activity coregulates quantal AMPA and NMDA currents at neocortical synapses. Neuron 26, 659–670 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Liao, D., Zhang, X., O'Brien, R., Ehlers, M. D. & Huganir, R. L. Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons. Nature Neurosci. 2, 37–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  118. Crump, F. T., Dillman, K. S. & Craig, A. M. cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors. J. Neurosci. 21, 5079–5088 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Rocha, M. & Sur, M. Rapid acquisition of dendritic spines by visual thalamic neurons after blockade of N-methyl-D-aspartate receptors. Proc. Natl Acad. Sci. USA 92, 8026–8030 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Marie, H., Morishita, W., Yu, X., Calakos, N. & Malenka, R. C. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45, 741–752 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Kauer, J. A. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol. 66, 447–475 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Borgland, S. L., Taha, S. A., Sarti, F., Fields, H. L. & Bonci, A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49, 589–601 (2006). The first paper to show a role for cocaine-induced insertion of NMDA channels and enhanced NMDAR-mediated neurotransmission in VTA dopamine neuron synapses as a mechanism mediating cocaine-induced synaptic plasticity.

    Article  CAS  PubMed  Google Scholar 

  124. Liu, Q. S., Pu, L. & Poo, M. M. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437, 1027–1031 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Saal, D., Dong, Y., Bonci, A. & Malenka, R. C. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37, 577–582 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Suvarna, N. et al. Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras. J. Biol. Chem. 280, 31450–31459 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Carpenter-Hyland, E. P., Woodward, J. J. & Chandler, L. J. Chronic ethanol induces synaptic but not extrasynaptic targeting of NMDA receptors. J. Neurosci. 24, 7859–7868 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mattson, M. P. Pathways towards and away from Alzheimer's disease. Nature 430, 631–639 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-b. Nature Neurosci. 8, 1051–1058 (2005). The first demonstration that acute application of amyloid-β 1–42 promotes internalization of NMDARs in cortical neurons in culture.

    Article  CAS  PubMed  Google Scholar 

  130. Hsieh, H. et al. AMPAR removal underlies Ab-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    Article  CAS  PubMed  Google Scholar 

  132. Sawa, A. & Snyder, S. H. Schizophrenia: diverse approaches to a complex disease. Science 296, 692–695 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Stefansson, H. et al. Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877–892 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Gu, Z., Jiang, Q., Fu, A. K., Ip, N. Y. & Yan, Z. Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J. Neurosci. 25, 4974–4984 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Hahn, C. G. et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Med. 12, 824–828 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Gerber, D. J. et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin γ subunit. Proc. Natl Acad. Sci. USA 100, 8993–8998 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Miyakawa, T. et al. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc. Natl Acad. Sci. USA 100, 8987–8992 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Braithwaite, S. P. et al. Regulation of NMDA receptor trafficking and function by striatal-enriched tyrosine phosphatase (STEP). Eur. J. Neurosci. 23, 2847–2856 (2006).

    Article  PubMed  Google Scholar 

  139. Engelman, H. S. & MacDermott, A. B. Presynaptic ionotropic receptors and control of transmitter release. Nature Rev. Neurosci. 5, 135–145 (2004).

    Article  CAS  Google Scholar 

  140. Thomas, C. G., Miller, A. J. & Westbrook, G. L. Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons. J. Neurophysiol. 95, 1727–1734 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5, 405–414 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Zhang, S. J. et al. Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron 53, 549–562 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Morishita, W. et al. Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression. Neuropharmacology 52, 71–76 (2006).

    Article  PubMed  CAS  Google Scholar 

  147. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Petralia, R. S., Sans, N., Wang, Y. X. & Wenthold, R. J. Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell. Neurosci. 29, 436–452 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Martin, J. H. Neuroanatomy: Text and Atlas 2nd edn (Appleton & Lange, Stamford, Connecticut, 1996).

    Google Scholar 

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Acknowledgements

The authors thank D. P. Purpura, M. V. L. Bennett, A. Z. Harris, B. D. Heifets, Y. R. Chin and members of the Zukin laboratory for reading earlier versions of the manuscript. Work supported by National Institutes of Health grant NS20752 to R.S.Z.

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C. Geoffrey Lau and R. Suzanne Zukin

NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Reviews Neuroscience 8, 413-426 (2007); doi:10.1038/nrn2153

R. Suzanne Zukin declares that she is the recipient of a small research grant from the Novo Nordisk A/S.

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Glossary

Long-term potentiation

(LTP). Activity-dependent strengthening of synaptic transmission that is long-lasting (usually more than one hour). Commonly induced by brief, high-frequency stimulation, LTP is widely believed to be a key cellular mechanism involved in learning and memory.

Long-term depression

(LTD). A long-lasting suppression of synaptic strength that is elicited by specific patterns of synaptic stimulation (for example, low-frequency stimulation). LTD is typically dependent on NMDA-receptor activation, and is widely believed to be a means of information storage in the brain.

Open probability

The fraction of time that a single channel remains open when fully activated by ligand or voltage.

Postsynaptic density

(PSD). An electron-dense specialization of excitatory postsynaptic membranes that contains a high concentration of glutamate receptors, ion channels, kinases, phosphatases and associated signalling and cytoskeletal proteins.

Ubiquitin–proteasome system

Ubiquitin is a 76 amino-acid protein that serves as a tag to mark proteins destined for degradation. Proteins tagged by a polyubiquitin chain are targeted to the proteasome, a large, multimeric barrel-like complex that acts by proteolysis to degrade proteins.

Exocyst complex

A macromolecular multimeric protein complex involved in directing cargo-loaded vesicles to sites of fusion in the plasma membrane; it is often concentrated at sites of active secretion and cell growth.

Plus-end-directed motor

Plus-end-directed motors transport cargo from the minus to the plus end of microtubules (in the anterograde direction, or from the neuronal cell body out into the neuronal process).

Extrasynaptic receptors

A receptor population located in a region of the dendritic or somatic membrane outside of the postsynaptic density and that is not activated by a single pulse of neurotransmitter release.

Excitatory postsynaptic potentials

(EPSPs). A transient postsynaptic membrane depolarization caused by presynaptic release of neurotransmitter.

PDZ domain

A modular protein interaction domain that is specialized for binding to carboxy-terminal peptide motifs of other proteins. Scaffolding and adaptor proteins that contain PDZ-domains mediate the assembly of large molecular complexes at specific subcellular sites, such as synapses. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD-95, discs large, zona occludens 1).

Clathrin-mediated

A form of receptor-mediated endocytosis, in which invagination of the endocytic vesicle is driven by the clathrin coat.

Autaptic cultures

Cultures in which hippocampal neurons are plated at an exceedingly sparse density so that each cell is physically isolated from other cells and makes synaptic connections only with itself.

Schaffer collateral–CA1 synapse

(Sch–CA1 synapse). Synapses formed by excitatory afferents from the CA3 to CA1 pyramidal cells in the hippocampus. LTP at this synapse is one of the most well-characterized forms of synaptic plasticity in the brain.

Metaplasticity

A higher-order plasticity than synaptic plasticity, metaplasticity ('plasticity of plasticity') refers to the phenomenon whereby previous synaptic activity (for example, prolonged changes in overall network activity over long time periods) or other external stimuli can influence (the occurrence of) subsequent synaptic plasticity (process or event).

Ocular dominance columns

In the mature primary visual cortex of mammals, most neurons respond predominantly to visual inputs from one eye or the other. Ocular dominance columns arise from the spatially organized, alternating columns of cells that receive sensory information from one eye or the other.

Orientation selectivity

Property of visual cortex neurons that enables the detection of bars and edges within visual images and the encoding of their orientations. As the cortex is organized in columns, neurons that belong to the same column share the same orientation tuning.

Barrel

A cylindrical column of neurons found in the rodent neocortex. Each barrel receives sensory input from a single whisker follicle, and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.

Silent synapse

An excitatory synapse containing functional NMDARs (N-methyl-D-aspartate receptors) but lacking AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). At the resting potential of the cell, NMDARs are blocked by extracellular Mg2+. To activate NMDARs, synaptically released glutamate must activate AMPARs, leading to Na+ influx and depolarization of the neuronal membrane, which in turn relieves block of NMDARs by Mg2+. The proportion of silent synapses at central synapses decreases during mammalian postnatal development.

Coatomer protein complex II

(COPII). The coat protein COPII forms carrier vesicles that mediate intracellular transport of newly synthesized proteins from exit sites of the endoplasmic reticulum to the cis face of the Golgi apparatus.

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Lau, C., Zukin, R. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8, 413–426 (2007). https://doi.org/10.1038/nrn2153

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