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Postsynaptic organisation and regulation of excitatory synapses


Dynamic regulation of synaptic efficacy is one of the mechanisms thought to underlie learning and memory. Many of the observed changes in efficacy, such as long-term potentiation and long-term depression, result from the functional alteration of excitatory neurotransmission mediated by postsynaptic glutamate receptors. These changes may result from the modulation of the receptors themselves and from regulation of protein networks associated with glutamate receptors. Understanding the interactions in this synaptic complex will yield invaluable insight into the molecular basis of synaptic function. This review focuses on the molecular organization of excitatory synapses and the processes involved in the dynamic regulation of glutamate receptors.

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Figure 1: Postsynaptic structure.
Figure 2: Dynamic regulation of postsynaptic structure.


  1. 1

    Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994).

    CAS  Article  Google Scholar 

  2. 2

    Pin, J. P. & Duvoisin, R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34, 1–26 (1995).

    CAS  Google Scholar 

  3. 3

    Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adaptor proteins. Science 278, 2075– 2080 (1997).

    CAS  Google Scholar 

  4. 4

    Ziff, E. B. Enlightening the postsynaptic density. Neuron 19, 1163–1174 (1997).

    CAS  PubMed  Google Scholar 

  5. 5

    Kennedy, M. B. Signal transduction molecules at the glutamatergic postsynaptic membrane. Brain Res. Brain Res. Rev. 26, 243– 257 (1998).

    CAS  PubMed  Google Scholar 

  6. 6

    Kim, J. H. & Huganir, R. L. Organization and regulation of proteins at synapses. Curr. Opin. Cell Biol. 11, 248–254 (1999).

    CAS  PubMed  Google Scholar 

  7. 7

    Ehlers, M. D., Mammen, A. L., Lau, L. F. & Huganir, R. L. Synaptic targeting of glutamate receptors. Curr. Opin. Cell Biol. 8, 484–489 ( 1996).

    CAS  PubMed  Google Scholar 

  8. 8

    Gomperts, S. N. Clustering membrane proteins: it's all coming together with the PSD- 95/SAP90 protein family. Cell 84, 659– 662 (1996).

    CAS  PubMed  Google Scholar 

  9. 9

    Sheng, M. PDZs and receptor/channel clustering: rounding up the latest suspects. Neuron 17, 575–578 ( 1996).

    CAS  PubMed  Google Scholar 

  10. 10

    Kornau, H. C., Seeburg, P. H. & Kennedy, M. B. Interaction of ion channels and receptors with PDZ domain proteins. Curr. Opin. Neurobiol. 7, 368–373 (1997).

    CAS  Google Scholar 

  11. 11

    Craven, S. E. & Bredt, D. S. PDZ proteins organize synaptic signaling pathways. Cell 93, 495– 498 (1998).

    CAS  Google Scholar 

  12. 12

    Doyle, D. A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 ( 1996).

    CAS  PubMed  Google Scholar 

  13. 13

    Songyang, Z. et al. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 275, 73– 77 (1997).

    CAS  PubMed  Google Scholar 

  14. 14

    Cho, K. O., Hunt, C. A. & Kennedy, M. B. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. Neuron 9, 929–942 ( 1992).

    CAS  Google Scholar 

  15. 15

    Kistner, U. et al. SAP90, a rat presynaptic protein related to the product of the Drosophila tumor suppressor gene dlg-A. J. Biol. Chem. 268, 4580–4583 ( 1993).

    CAS  PubMed  Google Scholar 

  16. 16

    Lue, R. A., Marfatia, S. M., Branton, D. & Chishti, A. H. Cloning and characterization of hdlg: the human homologue of the Drosophila discs large tumor suppressor binds to protein 4. 1. Proc. Natl Acad. Sci. USA 91, 9818– 9822 (1994).

    CAS  PubMed  Google Scholar 

  17. 17

    Muller, B. M. et al. Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein. J. Neurosci. 15, 2354–2366 (1995).

    CAS  PubMed  Google Scholar 

  18. 18

    Brenman, J. E., Christopherson, K. S., Craven, S. E., McGee, A. W. & Bredt, D. S. Cloning and characterization of postsynaptic density 93, a nitric oxide synthase interacting protein. J. Neurosci. 16, 7407–7415 (1996).

    CAS  PubMed  Google Scholar 

  19. 19

    Kim, E., Cho, K. O., Rothschild, A. & Sheng, M. Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins. Neuron 17 , 103–113 (1996).

    CAS  PubMed  Google Scholar 

  20. 20

    Muller, B. M. et al. SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo. Neuron 17, 255–265 (1996).

    CAS  PubMed  Google Scholar 

  21. 21

    Lahey, T., Gorczyca, M., Jia, X. X. & Budnik, V. The Drosophila tumor suppressor gene dlg is required for normal synaptic bouton structure . Neuron 13, 823–835 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Budnik, V. et al. Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg. Neuron 17, 627–640 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Tejedor, F. J. et al. Essential role for dlg in synaptic clustering of Shaker K+ channels in vivo. J. Neurosci. 17, 152–159 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Thomas, U. et al. Synaptic clustering of the cell adhesion molecule fasciclin II by discs-large and its role in the regulation of presynaptic structure. Neuron 19, 787– 799 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Zito, K., Fetter, R. D., Goodman, C. S. & Isacoff, E. Y. Synaptic clustering of Fascilin II and Shaker: essential targeting sequences and role of Dlg. Neuron 19, 1007– 1016 (1997).

    CAS  Google Scholar 

  26. 26

    Kornau, H. C., Schenker, L. T., Kennedy, M. B. & Seeburg, P. H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737– 1740 (1995).

    CAS  Google Scholar 

  27. 27

    Lau, L. F. et al. Interaction of the N-methyl-d-aspartate receptor complex with a novel synapse-associated protein, SAP102. J. Biol. Chem. 271, 21622–21628 ( 1996).

    CAS  PubMed  Google Scholar 

  28. 28

    Niethammer, M., Kim, E. & Sheng, M. Interaction between the C-terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J. Neurosci. 16, 2157–2163 (1996).

    CAS  PubMed  Google Scholar 

  29. 29

    Mori, H. et al. Role of the carboxy-terminal region of the GluR ɛ2 subunit in synaptic localization of the NMDA receptor channel. Neuron 21, 571–580 ( 1998).

    CAS  PubMed  Google Scholar 

  30. 30

    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 

  31. 31

    Steigerwald, F. et al. C-terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors. J. Neurosci. 20, 4573–4851 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Yamada, Y., Chochi, Y., Ko, J. A., Sobue, K. & Inui, M. Activation of channel activity of the NMDA receptor-PSD-95 complex by guanylate kinase-associated protein (GKAP). FEBS Lett. 458, 295–298 (1999).

    CAS  PubMed  Google Scholar 

  33. 33

    Yamada, Y., Chochi, Y., Takamiya, K., Sobue, K. & Inui, M. Modulation of the channel activity of the ɛ2/ζ1-subtype N-methyl d-aspartate receptor by PSD-95. J. Biol. Chem. 274, 6647–6652 ( 1999).

    CAS  PubMed  Google Scholar 

  34. 34

    Migaud, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (1998). The authors generated transgenic mice that had a targeted deletion after the second PDZ domain in PSD-95. The mutant mice had properly localized NMDA receptors and showed normal NMDA receptor function. However, synaptic plasticity was altered as indicated by an abnormal increase in LTP, which might contribute to the aberrant learning shown by the mutant mice. This study indicates that PSD-95 may organize signalling complexes in a NMDA receptor-mediated cascade distinct from PSD-95-dependent receptor localization.

    CAS  PubMed  Google Scholar 

  35. 35

    Brenman, J. E. et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains . Cell 84, 757–767 (1996).

    CAS  PubMed  Google Scholar 

  36. 36

    Christopherson, K. S., Hillier, B. J., Lim, W. A. & Bredt, D. S. PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J. Biol. Chem. 274, 27467–27473 (1999).

    CAS  PubMed  Google Scholar 

  37. 37

    Bredt, D. S. & Snyder, S. H. Nitric oxide, a novel neuronal messenger. Neuron 8, 3– 11 (1992).

    CAS  PubMed  Google Scholar 

  38. 38

    Schuman, E. M. & Madison, D. V. Nitric oxide and synaptic function. Annu. Rev. Neurosci. 17, 153–183 (1994).

    CAS  PubMed  Google Scholar 

  39. 39

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

    CAS  PubMed  Google Scholar 

  40. 40

    Chen, H. J., Rojas-Soto, M., Oguni, A. & Kennedy, M. B. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895–904 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Kim, J. H., Liao, D., Lau, L. F. & Huganir, R. L. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20, 683–691 ( 1998).A novel Ras-GTPase activating protein (synGAP) is found in a complex with NMDA receptors through association with PSD-95. SynGAP contains a C2 domain, which may regulate the functional characteristics of this molecule in response to calcium. SynGAP provides a mechanism by which NMDA receptor activation can be linked to Ras-mediated signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Finkbeiner, S. & Greenberg, M. E. Ca2+-dependent routes to Ras: mechanisms for neuronal survival, differentiation, and plasticity? Neuron 16, 233– 236 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Niethammer, M. et al. CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90. Neuron 20, 693 –707 (1998).

    CAS  Google Scholar 

  44. 44

    Furuyashiki, T. et al. Citron, a Rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus. J. Neurosci. 19, 109–118 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Zhang, W., Vazquez, L., Apperson, M. & Kennedy, M. B. Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. J. Neurosci. 19, 96– 108 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Irie, M. et al. Binding of neuroligins to PSD-95. Science 277, 1511–1515 (1997).

    CAS  Google Scholar 

  47. 47

    Ichtchenko, K. et al. Neuroligin 1: a splice site-specific ligand for β -neurexins. Cell 81, 435– 443 (1995).

    CAS  PubMed  Google Scholar 

  48. 48

    Hata, Y., Butz, S. & Sudhof, T. C. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J. Neurosci. 16, 2488– 2494 (1996).

    CAS  PubMed  Google Scholar 

  49. 49

    Butz, S., Okamoto, M. & Sudhof, T. C. A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94, 773–782 ( 1998).

    CAS  Google Scholar 

  50. 50

    Jo, K., Derin, R., Li, M. & Bredt, D.S. Characterization of MALS/Velis-1,-2, and-3: a family of mammalian LIN- 7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex. J. Neurosci. 19, 4189 –4199 (1999).

    CAS  PubMed  Google Scholar 

  51. 51

    Okamoto, M. & Sudhof, T. C. Mints, Munc18-interacting proteins in synaptic vesicle exocytosis. J. Biol. Chem. 272, 31459–31464 (1997).

    CAS  Google Scholar 

  52. 52

    Kaech, S. M., Whitfield, C. W. & Kim, S. K. The LIN-2/LIN-7/LIN-10 complex mediates basolateral membrane localization of the C. elegans EGF receptor LET-23 in vulval epithelial cells. Cell 94, 761– 771 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Kim, E. et al. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules . J. Cell Biol. 136, 669– 678 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Takeuchi, M. et al. SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J. Biol. Chem. 272, 11943–11951 (1997).

    CAS  PubMed  Google Scholar 

  55. 55

    Satoh, K. et al. DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95. Genes Cells 2, 415–424 (1997).

    CAS  PubMed  Google Scholar 

  56. 56

    Deguchi, M. et al. BEGAIN (brain-enriched guanylate kinase-associated protein), a novel neuronal PSD-95/SAP90-binding protein. J. Biol. Chem. 273, 26269–26272 (1998).

    CAS  PubMed  Google Scholar 

  57. 57

    Naisbitt, S. et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569–582 ( 1999).Identifies a novel protein (SHANK) that binds to GKAP and is found in a complex with NMDA receptors. SHANK can also form homomeric associations through interaction with an amino-terminal SAM domain. SHANK also binds cortactin, an actin- binding protein, through a proline-rich motif and may couple NMDA receptor activity to the regulation of postsynaptic microfilament structure.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Tu, J. C. et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23, 583–592 (1999).SHANK is also identified as a Homer- and mGlu receptor-interacting protein . This observation raises the possibility that NMDA receptors are linked to mGlu receptors through a chain that includes PSD-95, GKAP, SHANK and Homer.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Boeckers, T. M. et al. Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Biochem. Biophys. Res. Commun. 264, 247–252 (1999).

    CAS  PubMed  Google Scholar 

  60. 60

    Brakeman, P. R. et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284– 288 (1997).

    CAS  Google Scholar 

  61. 61

    Kato, A., Ozawa, F., Saitoh, Y., Hirai, K. & Inokuchi, K. vesl, a gene encoding VASP/Ena family related protein, is upregulated during seizure, long-term potentiation and synaptogenesis . FEBS Lett. 412, 183–189 (1997).

    CAS  PubMed  Google Scholar 

  62. 62

    Shiraishi, Y. et al. Cupidin, an isoform of Homer/Vesl, interacts with the actin cytoskeleton and activated rho family small GTPases and is expressed in developing mouse cerebellar granule cells. J. Neurosci. 19, 8389–8400 (1999).

    CAS  PubMed  Google Scholar 

  63. 63

    Bortolotto, Z. A., Bashir, Z. I., Davies, C. H. & Collingridge, G. L. A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation. Nature 368, 740–743 (1994).

    CAS  PubMed  Google Scholar 

  64. 64

    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).

    CAS  PubMed  Google Scholar 

  65. 65

    Wyszynski, M. et al. Competitive binding of α-actinin and calmodulin to the NMDA receptor. Nature 385, 439– 442 (1997).

    CAS  PubMed  Google Scholar 

  66. 66

    Ehlers, M. D., Fung, E. T., O'Brien, R. J. & Huganir, R. L. Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. J. Neurosci. 18, 720–730 (1998).

    CAS  PubMed  Google Scholar 

  67. 67

    Lin, J. W. et al. Yotiao: A novel protein of neuromuscular junction and brain that interacts with specific splice variants of NMDA receptor subunit NR1 . J. Neurosci. 18, 2017– 2027 (1998).

    CAS  PubMed  Google Scholar 

  68. 68

    Rosenmund, C. & Westbrook, G. L. Calcium-induced actin depolymerization reduces NMDA channel activity. Neuron 10, 805–814 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Ehlers, M. D., Zhang, S., Bernhardt, J. P. & Huganir, R. L. Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84, 745– 755 (1996).

    CAS  PubMed  Google Scholar 

  70. 70

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

    CAS  PubMed  Google Scholar 

  71. 71

    Naisbitt, S. et al. Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein . J. Neurosci. 20, 4524– 4534 (2000).

    CAS  PubMed  Google Scholar 

  72. 72

    Setou, M., Nakagawa, T., Seog, S.-H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796– 1802 (2000).Identifies a novel, neuron-specific microtubule motor protein (KIF17) that is found in a complex with Mint, CASK and NR2B. This protein complex is localized to vesicles, and is proposed to transport NMDA receptors within dendrites. Interestingly, PSD-95 is not associated with this complex, indicating a specific postsynaptic role for PSD-95 in NMDA receptor function.

    CAS  Google Scholar 

  73. 73

    Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279– 284 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Srivastava, S. et al. Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP. Neuron 21, 581–591 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Dong, H. et al. Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. J. Neurosci. 19, 6930– 6941 (1999).

    CAS  PubMed  Google Scholar 

  76. 76

    Xia, J., Zhang, X., Staudinger, J. & Huganir, R. L. Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1. Neuron 22, 179–187 (1999).

    CAS  Google Scholar 

  77. 77

    Dev, K. K., Nishimune, A., Henley, J. M. & Nakanishi, S. The protein kinase C α-binding protein PICK1 interacts with short but not long form alternative splice variants of AMPA receptor subunits. Neuropharmacology 38, 635–644 (1999).

    CAS  PubMed  Google Scholar 

  78. 78

    Leonard, A. S., Davare, M. A., Horne, M. C., Garner, C. C. & Hell, J. W. SAP97 is associated with the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J. Biol. Chem. 273, 19518– 19524 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Rongo, C., Whitfield, C. W., Rodal, A., Kim, S. K. & Kaplan, J. M. LIN-10 is a shared component of the polarized protein localization pathways in neurons and epithelia. Cell 94, 751–759 ( 1998).This report describes the necessity of a PDZ-containing protein (Lin-10) in correctly localizing the C. elegans glutamate receptor GLR-1 in both neurons and epithelial cells. These data reinforce previous studies indicating that epithelial cells and neurons share some common methods for protein sorting.

    CAS  PubMed  Google Scholar 

  80. 80

    Torres, R. et al. PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 1453–1463 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Bruckner, K. et al. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22, 511 –524 (1999).

    CAS  Google Scholar 

  82. 82

    Ye, B. et al. GRASP-1: A neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron 26, 603– 617 (2000).

    CAS  PubMed  Google Scholar 

  83. 83

    O'Brien, R. J. et al. Synaptic clustering of AMPA receptors by the extracellular immediate gene product NARP. Neuron 23, 309–323 (1999).

    CAS  Google Scholar 

  84. 84

    Osten, P. et al. The AMPA receptor GluR2 C-terminus can mediate a reversible, ATP-dependent interaction with NSF and α- and β-SNAPs . Neuron 21, 99–110 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 ( 1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Song, I. et al. Interaction of the N-ethylmaleimide sensitive factor with AMPA receptors. Neuron 21, 393– 400 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Hosokawa, T., Rusakov, D. A., Bliss, T. V. & Fine, A. Repeated confocal imaging of individual dendritic spines in the living hippocampal slice: evidence for changes in length and orientation associated with chemically induced LTP. J. Neurosci. 15, 5560– 5573 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Halpain, S., Hipolito, A. & Saffer, L. Regulation of F-actin stability in dendritic spines by glutamate receptors and calcineurin. J. Neurosci. 18, 9835–9844 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Maletic-Savatic, M., Malinow, R. & Svoboda, K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Bear, M. F. & Malenka, R. C. Synaptic plasticity: LTP and LTD. Curr. Opin. Neurobiol. 4, 389– 399 (1994).

    CAS  PubMed  Google Scholar 

  91. 91

    Linden, D. J. Long-term synaptic depression in the mammalian brain. Neuron 12, 457–472 (1994).

    CAS  PubMed  Google Scholar 

  92. 92

    Bear, M. F. & Abraham, W. C. Long-term depression in hippocampus . Annu. Rev. Neurosci. 19, 437– 462 (1996).

    CAS  PubMed  Google Scholar 

  93. 93

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

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J. & Huganir, R. L. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 ( 1996).

    CAS  PubMed  Google Scholar 

  96. 96

    Barria, A., Derkach, V. & Soderling, T. Identification of the Ca2+/calmodulin-dependent protein kinase II regulatory phosphorylation site in the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptor. J. Biol. Chem. 272, 32727–32730 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Mammen, A. L., Kameyama, K., Roche, K. W. & Huganir, R. Phosphorylation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit by calcium/calmodulin-dependent kinase II. J. Biol. Chem. 272, 32528–32533 (1997).

    CAS  Google Scholar 

  98. 98

    Derkach, V., Barria, A. & Soderling, T. R. Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl Acad. Sci. USA 96, 3269–3274 (1999).

    CAS  Google Scholar 

  99. 99

    Soderling, T. R. & Derkach, V. A. Postsynaptic protein phosphorylation and LTP. Trends Neurosci. 23 , 75–80 (2000).

    CAS  PubMed  Google Scholar 

  100. 100

    Lee, H.-K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 ( 2000).The authors show that changes in synaptic efficacy correlate with changes in the phosphorylation state of the GluR1 AMPA receptor subunit. The induction of LTP results in an increase in the phosphorylation of Ser 831. In contrast, the expression of LTD results in a decrease in the phosphorylation of Ser 845.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Isaac, J. T., Nicoll, R. A. & Malenka, R. C. Evidence for silent synapses: implications for the expression of LTP. Neuron 15, 427– 434 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Liao, D., Hessler, N. A. & Malinow, R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature 375, 400–404 ( 1995).

    CAS  Google Scholar 

  103. 103

    Durand, G., Kovalchuk, Y. & Konnerth, A. Long term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71 –75 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Gomperts, S. N., Rao, A., Craig, A. M., Malenka, R. C. & Nicoll, R. A. Postsynaptically silent synapses in single neuron cultures. Neuron 21, 1443– 1451 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21 , 545–559 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    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). Expression of LTP through NMDA receptor activation leads to the acquisition of AMPA receptor responses and a reduction in the number of silent synapses. Here the authors describe a morphological correlate to these observations in cultured neurons. NMDA receptor activation results in an increase in the number of synaptic AMPA receptor clusters, which colocalize with NMDA receptors, indicating that these synapses are no longer silent.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Petralia, R. S. et al. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nature Neurosci. 2, 31–36 (1999 ).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Shi, S. H. et al. Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284 , 1811–1816 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Carroll, R. C., Lissin, D. V., von Zastrow, M., Nicoll, R. A. & Malenka, R. C. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nature Neurosci. 2, 454–460 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Luscher, C. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24, 649– 658 (1999).

    CAS  PubMed  Google Scholar 

  111. 111

    Man, Y. H. et al. Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25, 649–662 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Wang, Y. T. & Linden, D. J. Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 25, 635–647 ( 2000).Shows a conclusive link between LTD expression and the internalization of AMPA receptors in cultured Purkinje cells. Internalization of AMPA receptors seems to occur through clathrin-mediated endocytosis. Indeed, stimulating AMPA receptor endocytosis or expressing LTD mutually occlude each other, indicating that the processes are related.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Luthi, A. et al. Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF–GluR2 interaction. Neuron 24, 389–399 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000). Expression of LTP or increasing the activity of CaMKII results in the delivery of tagged GluR1 AMPA receptors to the synapse surface. Delivery is dependent on a PDZ domain-mediated interaction, as mutating the PDZ domain at the GluR1 carboxyl terminus abolishes efficient delivery.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Li, P. et al. AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nature Neurosci. 2, 972– 977 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Chung, H. J., Kim, C.-H., Lee, H.-K., Xia, J. & Huganir, R. L. Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long term–depression. Neuron (in the press).

  117. 117

    Linden, D. J., Chung, H. J., Xia, J. & Huganir, R. L. Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron (submitted).

  118. 118

    Liu, S.-Q. J. & Cull-Candy, S. G. Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405, 454– 458 (2000).Describes a novel form of plasticity in cerebellar stellate cells that seems to be due to changes in AMPA receptor-subunit composition. Activation of AMPA receptors results in a decrease in AMPA receptor-mediated calcium permeability, and an increase in the amplitude of excitatory postsynaptic currents. Changes in synaptic efficacy may be due to the activity-induced delivery of AMPA receptors that are not calcium-permeable.

    CAS  PubMed  Google Scholar 

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The ability to sense the simultaneous occurrence of synaptic activity at different points of the same cell.


Src-homology region 3 domains. Protein sequences of about 50 amino acids that recognize and bind sequences rich in proline.


A group of proteins involved in growth, differentiation and cellular signalling that require the binding of GTP to enter into their active state.


A Ras-related GTPase involved in controlling the polymerization of actin.


Cytoskeletal protein that attaches other cytoskeletal elements to integral membrane proteins.


(or Pentaxin) Protein of discoid appearance under the electron microscope, consisting of five non-covalently bound subunits.


Protein involved in the formation of microtubule bundles and in membrane trafficking.


A major constituent of the coat associated with coated vesicles, particles involved in membrane trafficking.


The property whereby current through a channel does not flow with the same ease from the inside as from the outside. In inward rectification, for instance, current into the cell flows more easily than out of the cell through the same population of channels.


A plot of the changes of ionic current as a function of membrane voltage.

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Scannevin, R., Huganir, R. Postsynaptic organisation and regulation of excitatory synapses. Nat Rev Neurosci 1, 133–141 (2000).

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