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  • Review Article
  • Published:

Cell adhesion molecules: signalling functions at the synapse

Nature Reviews Neuroscience volume 8, pages 206–220 (2007)Cite this article

Key Points

  • Cell adhesion molecules are present at synaptic sites throughout the lifetime of a synapse and are involved in the formation, function and plasticity of synaptic connections.

  • Synaptically localized cell adhesion molecules (SAMs), are multifunctional molecules that coordinate different aspects of synaptic development and function through specialized signalling or protein–protein interaction motifs.

  • Neurexin–neuroligin signalling has a role in the development of pre- and postsynaptic terminals at both excitatory and inhibitory synapses. Recent in vivo data indicates that these molecules are most important for the proper maturation and function of synaptic contacts.

  • The EphB receptor tyrosine kinase regulates excitatory synaptogenesis, including the clustering of NMDARs (N-methyl-D-aspartate receptors) and AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), dendritic spine formation and presynaptic differentiation. EphB-mediated signalling seems to be particularly significant for a subset of synaptic inputs in vivo.

  • A number of molecules belonging to the immunoglobulin superfamily of proteins (synaptic cell adhesion molecule (SynCAM), synaptic adhesion-like molecule (SALM) and netrin G2 ligand (NGL2)) also contain intracellular PDZ binding domains that permit interactions with the postsynaptic scaffold protein PSD-95 (postsynaptic density protein-95). Each of these trans-synaptic signals can control aspects of excitatory synapse formation in vitro.

  • Cadherins signal via catenins to regulate dendritic spine morphology and motility. In addition, in vivo work has shown that the loss of particular catenin molecules results in abnormal synapse formation and/or maturation.

  • Ephs and ephrins regulate two mechanistically distinct forms of long-term potentiation in the hippocampus. At the mossy fibre–CA3 synapse this occurs downstream of a transynaptic interaction between postsynaptic EphB and presynaptic ephrin-B, whereas at the Schaeffer collateral–CA1 synapse the mechanism is less clear.

  • Multiple lines of evidence indicate that neural cell adhesion molecule and cadherin regulate hippocampal synaptic plasticity. Both molecules possess multiple adhesive and signalling functions that could be important for plasticity, but the exact mechanisms by which these molecules regulate these functions are not clear.

Abstract

Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre- and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.

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Figure 1: Synaptic adhesion molecules function throughout the life of a synapse.
Figure 2: Neurexin–neuroligin splice code and synapse formation.
Figure 3: Trans-synaptic signalling during synaptogenesis: in vitro evidence.

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References

  1. Li, Z. & Sheng, M. Some assembly required: the development of neuronal synapses. Nature Rev. Mol. Cell. Biol. 4, 833–841 (2003).

    Article  CAS  Google Scholar 

  2. Waites, C. L., Craig, A. M. & Garner, C. C. Mechanisms of vertebrate synaptogenesis. Annu. Rev. Neurosci. 28, 251–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Kayser, M. S. & Dalva, M. B. in Textbook of Neural Repair and Rehabilitation Vol.1 (eds Selzer, M. E., Cohen, L. G., Gage, F. H., Clarke, S. & Duncan, P. W.) 346–361 (Cambridge Univ. Press, Cambridge, 2006).

    Book  Google Scholar 

  4. Nguyen, T. & Sudhof, T. C. Binding properties of neuroligin 1 and neurexin 1β reveal function as heterophilic cell adhesion molecules. J. Biol. Chem. 272, 26032–26039 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Ushkaryov, Y. A., Petrenko, A. G., Geppert, M. & Sudhof, T. C. Neurexins: synaptic cell surface proteins related to the α-latrotoxin receptor and laminin. Science 257, 50–56 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Song, J. Y., Ichtchenko, K., Sudhof, T. C. & Brose, N. Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc. Natl Acad. Sci. USA 96, 1100–1105 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ullrich, B., Ushkaryov, Y. A. & Sudhof, T. C. Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14, 497–507 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Missler, M. & Sudhof, T. C. Neurexins: three genes and 1001 products. Trends Genet. 14, 20–26 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Ushkaryov, Y. A. & Sudhof, T. C. Neurexin III α: extensive alternative splicing generates membrane-bound and soluble forms. Proc. Natl Acad. Sci. USA 90, 6410–6414 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rudenko, G., Nguyen, T., Chelliah, Y., Sudhof, T. C. & Deisenhofer, J. The structure of the ligand-binding domain of neurexin Iβ: regulation of LNS domain function by alternative splicing. Cell 99, 93–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Boucard, A. A., Chubykin, A. A., Comoletti, D., Taylor, P. & Sudhof, T. C. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron 48, 229–236 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Chih, B., Gollan, L. & Scheiffele, P. Alternative splicing controls selective trans-synaptic interactions of the neuroligin–neurexin complex. Neuron 51, 171–178 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Biederer, T. & Sudhof, T. C. Mints as adaptors. Direct binding to neurexins and recruitment of munc18. J. Biol. Chem. 275, 39803–39806 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Chih, B., Engelman, H. & Scheiffele, P. Control of excitatory and inhibitory synapse formation by neuroligins. Science 307, 1324–1328 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Prange, O., Wong, T. P., Gerrow, K., Wang, Y. T. & El-Husseini, A. A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc. Natl Acad. Sci. USA 101, 13915–13920 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Levinson, J. N. et al. Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-1β in neuroligin-induced synaptic specificity. J. Biol. Chem. 280, 17312–17319 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Graf, E. R., Zhang, X., Jin, S. X., Linhoff, M. W. & Craig, A. M. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119, 1013–1026 (2004). Together with reference 17, this paper shows that neurexin–neuroligin interactions induce pre- and postsynaptic differentiation at both excitatory and inhibitory neuronal contacts in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Scheiffele, P., Fan, J., Choih, J., Fetter, R. & Serafini, T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669 (2000). Establishes the use of a heterologous cell co-culture of neurons with transfected non-neuronal cells to demonstrate the ability of a molecule — in this case neuroligin — to induce clustering of presynaptic machinery in contacting axons.

    Article  CAS  PubMed  Google Scholar 

  22. Nam, C. I. & Chen, L. Postsynaptic assembly induced by neurexin–neuroligin interaction and neurotransmitter. Proc. Natl Acad. Sci. USA 102, 6137–6142 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Varoqueaux, F., Jamain, S. & Brose, N. Neuroligin 2 is exclusively localized to inhibitory synapses. Eur. J. Cell Biol. 83, 449–456 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Graf, E. R., Kang, Y., Hauner, A. M. & Craig, A. M. Structure function and splice site analysis of the synaptogenic activity of the neurexin-1β LNS domain. J. Neurosci. 26, 4256–4265 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Biederer, T. & Sudhof, T. C. CASK and protein 4.1 support F-actin nucleation on neurexins. J. Biol. Chem. 276, 47869–47876 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Dean, C. et al. Neurexin mediates the assembly of presynaptic terminals. Nature Neurosci. 6, 708–716 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  Google Scholar 

  29. Rao, A., Kim, E., Sheng, M. & Craig, A. M. Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture. J. Neurosci. 18, 1217–1229 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Gerrow, K. et al. A preformed complex of postsynaptic proteins is involved in excitatory synapse development. Neuron 49, 547–562 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Varoqueaux, F. et al. Neuroligins determine synapse maturation and function. Neuron 51, 741–754 (2006). This recent study found that the absence of neuroligins 1–3 in vivo does not result in abnormal formation of synaptic contacts, but rather a defect in the maturation of synapses and impaired synaptic transmission.

    Article  CAS  PubMed  Google Scholar 

  33. Laumonnier, F. et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am. J. Hum. Genet. 74, 552–557 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet. 34, 27–29 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Chih, B., Afridi, S. K., Clark, L. & Scheiffele, P. Disorder-associated mutations lead to functional inactivation of neuroligins. Hum. Mol. Genet. 13, 1471–1477 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Missler, M. et al. α-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423, 939–948 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Gale, N. W. et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9–19 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y. & Pasquale, E. B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature Neurosci. 6, 153–160 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Buchert, M. et al. The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell–cell contact in the brain. J. Cell Biol. 144, 361–371 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kullander, K. & Klein, R. Mechanisms and functions of Eph and ephrin signalling. Nature Rev. Mol. Cell Biol. 3, 475–486 (2002).

    Article  CAS  Google Scholar 

  41. Cowan, C. A. & Henkemeyer, M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413, 174–179 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Dalva, M. B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000). The authors demonstrate that the EphB receptor tyrosine kinase interacts directly with the NMDAR. Clustering and activation of EphB with a soluble ephrin-B ligand induces clustering of NMDARs and the formation of presynaptic terminals.

    Article  CAS  PubMed  Google Scholar 

  44. Henkemeyer, M., Itkis, O. S., Ngo, M., Hickmott, P. W. & Ethell, I. M. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J. Cell Biol. 163, 1313–1326 (2003). Shows that neurons from mice lacking EphB1–3 have a near total absence of excitatory synapses and spines in vitro , and reduced spine density and size in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Grunwald, I. C. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 1027–1040 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Contractor, A. et al. Trans-synaptic Eph receptor–ephrin signaling in hippocampal mossy fiber LTP. Science 296, 1864–1869 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Grunwald, I. C. et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nature Neurosci. 7, 33–40 (2004). Identified a role for ephrin-B family members in hippocampal LTP. Mice lacking ephrin-B2 and ephrin-B3 have defects in hippocampal LTP. However, like EphB receptors, ephrin-B ligands are primarily localized postsynaptically at CA3 synapses and regulate LTP independent of their intracellular domains.

    Article  CAS  PubMed  Google Scholar 

  48. Rodenas-Ruano, A., Perez-Pinzon, M. A., Green, E. J., Henkemeyer, M. & Liebl, D. J. Distinct roles for ephrinB3 in the formation and function of hippocampal synapses. Dev. Biol. 292, 34–45 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB–EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Kayser, M. S., McClelland, A. C., Hughes, E. G. & Dalva, M. B. Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors. J. Neurosci. 26, 12152–12164 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ethell, I. M. et al. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001–1013 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Ethell, I. M. & Yamaguchi, Y. Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons. J. Cell Biol. 144, 575–586 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Irie, F. & Yamaguchi, Y. EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nature Neurosci. 5, 1117–1118 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Moeller, M. L., Shi, Y., Reichardt, L. F. & Ethell, I. M. EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of focal adhesion kinase and RhoA activation. J. Biol. Chem. 281, 1587–1598 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Henderson, J. T. et al. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041–1056 (2001). Along with reference 45, this paper demonstrates that EphB2 is required for hippocampal synaptic plasticity and suggests that this occurs through interactions with NMDARs.

    Article  CAS  PubMed  Google Scholar 

  56. Rougon, G. & Hobert, O. New insights into the diversity and function of neuronal immunoglobulin superfamily molecules. Annu. Rev. Neurosci. 26, 207–238 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Biederer, T. et al. SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 297, 1525–1531 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, C. Y. et al. A novel family of adhesion-like molecules that interacts with the NMDA receptor. J. Neurosci. 26, 2174–2183 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ko, J. et al. SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses. Neuron 50, 233–245 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Kim, S. et al. NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation. Nature Neurosci. 9, 1294–1301 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Uryu, K., Butler, A. K. & Chesselet, M. F. Synaptogenesis and ultrastructural localization of the polysialylated neural cell adhesion molecule in the developing striatum. J. Comp. Neurol. 405, 216–232 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Dityatev, A., Dityateva, G. & Schachner, M. Synaptic strength as a function of post- versus presynaptic expression of the neural cell adhesion molecule NCAM. Neuron 26, 207–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Dityatev, A. et al. Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses. J. Neurosci. 24, 9372–9382 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yamagata, M., Weiner, J. A. & Sanes, J. R. Sidekicks: synaptic adhesion molecules that promote lamina-specific connectivity in the retina. Cell 110, 649–660 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Shen, K. & Bargmann, C. I. The immunoglobulin superfamily protein SYG-1 determines the location of specific synapses in C. elegans. Cell 112, 619–630 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Shen, K., Fetter, R. D. & Bargmann, C. I. Synaptic specificity is generated by the synaptic guidepost protein SYG-2 and its receptor, SYG-1. Cell 116, 869–881 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Ango, F. et al. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment. Cell 119, 257–272 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Takeichi, M. Morphogenetic roles of classic cadherins. Curr. Opin. Cell Biol. 7, 619–627 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Vaughn, D. E. & Bjorkman, P. J. The (Greek) key to structures of neural adhesion molecules. Neuron 16, 261–273 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Geiger, B. & Ayalon, O. Cadherins. Annu. Rev. Cell Biol. 8, 307–332 (1992).

    Article  CAS  PubMed  Google Scholar 

  71. Fannon, A. M. & Colman, D. R. A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins. Neuron 17, 423–434 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Yamagata, M., Herman, J. P. & Sanes, J. R. Lamina-specific expression of adhesion molecules in developing chick optic tectum. J. Neurosci. 15, 4556–4571 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jou, T. S., Stewart, D. B., Stappert, J., Nelson, W. J. & Marrs, J. A. Genetic and biochemical dissection of protein linkages in the cadherin–catenin complex. Proc. Natl Acad. Sci. USA 92, 5067–5071 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Koch, A. W., Pokutta, S., Lustig, A. & Engel, J. Calcium binding and homoassociation of E-cadherin domains. Biochemistry 36, 7697–7705 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Shan, W. S. et al. Functional cis-heterodimers of N- and R-cadherins. J. Cell Biol. 148, 579–590 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Togashi, H. et al. Cadherin regulates dendritic spine morphogenesis. Neuron 35, 77–89 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Elste, A. M. & Benson, D. L. Structural basis for developmentally regulated changes in cadherin function at synapses. J. Comp. Neurol. 495, 324–335 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Nuriya, M. & Huganir, R. L. Regulation of AMPA receptor trafficking by N-cadherin. J. Neurochem. 97, 652–661 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Murase, S., Mosser, E. & Schuman, E. M. Depolarization drives β-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35, 91–105 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Sara, Y. et al. Selective capability of SynCAM and neuroligin for functional synapse assembly. J. Neurosci. 25, 260–270 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Elia, L. P., Yamamoto, M., Zang, K. & Reichardt, L. F. p120 catenin regulates dendritic spine and synapse development through Rho-family GTPases and cadherins. Neuron 51, 43–56 (2006). These authors report that gene deletion of p120 catenin causes reduced density of both spines and synapses in vivo , and results in global changes in both Rac1 and RhoA activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Abe, K., Chisaka, O., Van Roy, F. & Takeichi, M. Stability of dendritic spines and synaptic contacts is controlled by α N-catenin. Nature Neurosci. 7, 357–363 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Bamji, S. X. et al. Role of β-catenin in synaptic vesicle localization and presynaptic assembly. Neuron 40, 719–731 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hessler, N. A., Shirke, A. M. & Malinow, R. The probability of transmitter release at a mammalian central synapse. Nature 366, 569–572 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Nicoll, R. A. & Malenka, R. C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Jorntell, H. & Hansel, C. Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses. Neuron 52, 227–238 (2006).

    Article  PubMed  CAS  Google Scholar 

  87. Dityatev, A. & Schachner, M. The extracellular matrix and synapses. Cell Tissue Res. 326, 647–654 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Zhang, W. et al. Extracellular domains of α-neurexins participate in regulating synaptic transmission by selectively affecting N- and P/Q-type Ca2+ channels. J. Neurosci. 25, 4330–4342 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liebl, D. J., Morris, C. J., Henkemeyer, M. & Parada, L. F. mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and adult mouse central nervous system. J. Neurosci. Res. 71, 7–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Takasu, M. A., Dalva, M. B., Zigmond, R. E. & Greenberg, M. E. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491–495 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Irie, F., Okuno, M., Pasquale, E. B. & Yamaguchi, Y. EphrinB–EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nature Cell Biol. 7, 501–509 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Weisskopf, M. G. & Nicoll, R. A. Presynaptic changes during mossy fibre LTP revealed by NMDA receptor-mediated synaptic responses. Nature 376, 256–259 (1995).

    Article  CAS  PubMed  Google Scholar 

  93. Armstrong, J. N. et al. B-ephrin reverse signaling is required for NMDA-independent long-term potentiation of mossy fibers in the hippocampus. J. Neurosci. 26, 3474–3481 (2006). Together with reference 46, this paper provides the most elegant example of a trans-synaptic signal regulating long-term synaptic plasticity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Mayford, M., Barzilai, A., Keller, F., Schacher, S. & Kandel, E. R. Modulation of an NCAM-related adhesion molecule with long-term synaptic plasticity in Aplysia. Science 256, 638–644 (1992).

    Article  CAS  PubMed  Google Scholar 

  96. Bailey, C. H., Chen, M., Keller, F. & Kandel, E. R. Serotonin-mediated endocytosis of apCAM: an early step of learning-related synaptic growth in Aplysia. Science 256, 645–649 (1992).

    Article  CAS  PubMed  Google Scholar 

  97. Luthi, A., Laurent, J. P., Figurov, A., Muller, D. & Schachner, M. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779 (1994). This paper was the first to identify a role for cell adhesion molecules in hippocampal synaptic plasticity. The authors demonstrate that application of antibodies or peptides that disrupt NCAM- or L1-mediated adhesion reduce hippocampal LTP.

    Article  PubMed  Google Scholar 

  98. Murai, K. K., Misner, D. & Ranscht, B. Contactin supports synaptic plasticity associated with hippocampal long-term depression but not potentiation. Curr. Biol. 12, 181–190 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Ronn, L. C., Bock, E., Linnemann, D. & Jahnsen, H. NCAM-antibodies modulate induction of long-term potentiation in rat hippocampal CA1. Brain Res. 677, 145–151 (1995).

    Article  CAS  PubMed  Google Scholar 

  100. Cambon, K., Venero, C., Berezin, V., Bock, E. & Sandi, C. Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning. Neuroscience 122, 183–191 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Muller, D. et al. PSA–NCAM is required for activity-induced synaptic plasticity. Neuron 17, 413–422 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Muller, D. et al. Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid–neural cell adhesion molecule-deficient hippocampus. Proc. Natl Acad. Sci. USA 97, 4315–4320 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bukalo, O. et al. Conditional ablation of the neural cell adhesion molecule reduces precision of spatial learning, long-term potentiation, and depression in the CA1 subfield of mouse hippocampus. J. Neurosci. 24, 1565–1577 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Holst, B. D. et al. Allosteric modulation of AMPA-type glutamate receptors increases activity of the promoter for the neural cell adhesion molecule, N-CAM. Proc. Natl Acad. Sci. USA 95, 2597–2602 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cremer, H. et al. Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367, 455–459 (1994).

    Article  CAS  PubMed  Google Scholar 

  106. Cremer, H. et al. Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice. Proc. Natl Acad. Sci. USA 95, 13242–13247 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cremer, H., Chazal, G., Goridis, C. & Represa, A. NCAM is essential for axonal growth and fasciculation in the hippocampus. Mol. Cell. Neurosci. 8, 323–335 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Gass, P. et al. Deficits in memory tasks of mice with CREB mutations depend on gene dosage. Learn. Mem. 5, 274–288 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Kang, H., Welcher, A. A., Shelton, D. & Schuman, E. M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653–664 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Finne, J., Finne, U., Deagostini-Bazin, H. & Goridis, C. Occurrence of α 2–8 linked polysialosyl units in a neural cell adhesion molecule. Biochem. Biophys. Res. Commun. 112, 482–487 (1983).

    Article  CAS  PubMed  Google Scholar 

  111. Kiss, J. Z. et al. Activity-dependent mobilization of the adhesion molecule polysialic NCAM to the cell surface of neurons and endocrine cells. EMBO J. 13, 5284–5292 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schuster, T., Krug, M., Hassan, H. & Schachner, M. Increase in proportion of hippocampal spine synapses expressing neural cell adhesion molecule NCAM180 following long-term potentiation. J. Neurobiol. 37, 359–372 (1998).

    Article  CAS  PubMed  Google Scholar 

  113. Becker, C. G. et al. The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. J. Neurosci. Res. 45, 143–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Venero, C. et al. Hippocampal up-regulation of NCAM expression and polysialylation plays a key role on spatial memory. Eur. J. Neurosci. 23, 1585–1595 (2006).

    Article  PubMed  Google Scholar 

  115. Eckhardt, M. et al. Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity. J. Neurosci. 20, 5234–5244 (2000). Along with reference 101, this paper demonstrates that the post-translational addition of PSA to NCAM is required for LTP. Either enzymatic removal of PSA (reference 101) or genetic ablation of the enzyme required for PSA addition (reference 115) results in reduced LTP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rutishauser, U. Polysialic acid and the regulation of cell interactions. Curr. Opin. Cell Biol. 8, 679–684 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. Vaithianathan, T. et al. Neural cell adhesion molecule-associated polysialic acid potentiates α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor currents. J. Biol. Chem. 279, 47975–47984 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Hoffman, K. B., Larson, J., Bahr, B. A. & Lynch, G. Activation of NMDA receptors stimulates extracellular proteolysis of cell adhesion molecules in hippocampus. Brain Res. 811, 152–155 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Wechsler, A. & Teichberg, V. I. Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J. 17, 3931–3939 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sytnyk, V. et al. Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuron-to-neuron contacts. J. Cell Biol. 159, 649–661 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sytnyk, V., Leshchyns'ka, I., Nikonenko, A. G. & Schachner, M. NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J. Cell Biol. 174, 1071–1085 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cambon, K. et al. A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. J. Neurosci. 24, 4197–4204 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Beggs, H. E., Baragona, S. C., Hemperly, J. J. & Maness, P. F. NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). J. Biol. Chem. 272, 8310–8319 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Beesley, P. W., Mummery, R. & Tibaldi, J. N-cadherin is a major glycoprotein component of isolated rat forebrain postsynaptic densities. J. Neurochem. 64, 2288–2294 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Uchida, N., Honjo, Y., Johnson, K. R., Wheelock, M. J. & Takeichi, M. The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J. Cell Biol. 135, 767–779 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Bozdagi, O., Shan, W., Tanaka, H., Benson, D. L. & Huntley, G. W. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron 28, 245–259 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Tang, L., Hung, C. P. & Schuman, E. M. A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation. Neuron 20, 1165–1175 (1998). The authors demonstrate that the treatment of hippocampal slices with antibodies or peptides that disrupt cadherin binding reduces hippocampal LTP.

    Article  CAS  PubMed  Google Scholar 

  128. Yamagata, K. et al. Arcadlin is a neural activity-regulated cadherin involved in long term potentiation. J. Biol. Chem. 274, 19473–19479 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Jungling, K. et al. N-cadherin transsynaptically regulates short-term plasticity at glutamatergic synapses in embryonic stem cell-derived neurons. J. Neurosci. 26, 6968–6978 (2006).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  130. Manabe, T. et al. Loss of cadherin-11 adhesion receptor enhances plastic changes in hippocampal synapses and modifies behavioral responses. Mol. Cell. Neurosci. 15, 534–546 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Edsbagge, J. et al. Expression of dominant negative cadherin in the adult mouse brain modifies rearing behavior. Mol. Cell. Neurosci. 25, 524–535 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Tanaka, H. et al. Molecular modification of N-cadherin in response to synaptic activity. Neuron 25, 93–107 (2000). Shows that synaptic activity results in the dimerization and protease resistance of cadherin. These changes are indicative of enhanced cadherin-mediated adhesion.

    Article  CAS  PubMed  Google Scholar 

  133. Israely, I. et al. Deletion of the neuron-specific protein δ-catenin leads to severe cognitive and synaptic dysfunction. Curr. Biol. 14, 1657–1663 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Park, C., Falls, W., Finger, J. H., Longo-Guess, C. M. & Ackerman, S. L. Deletion in Catna2, encoding α N-catenin, causes cerebellar and hippocampal lamination defects and impaired startle modulation. Nature Genet. 31, 279–284 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Xia, J., Chung, H. J., Wihler, C., Huganir, R. L. & Linden, D. J. Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron 28, 499–510 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Terashima, A. et al. Regulation of synaptic strength and AMPA receptor subunit composition by PICK1. J. Neurosci. 24, 5381–5390 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Steinberg, J. P. et al. Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron 49, 845–860 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Kim, C. H., Chung, H. J., Lee, H. K. & Huganir, R. L. Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. Proc. Natl Acad. Sci. USA 98, 11725–11730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 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).

    Article  CAS  PubMed  Google Scholar 

  140. Daw, M. I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873–886 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Arami, S., Jucker, M., Schachner, M. & Welzl, H. The effect of continuous intraventricular infusion of L1 and NCAM antibodies on spatial learning in rats. Behav. Brain Res. 81, 81–87 (1996).

    Article  CAS  PubMed  Google Scholar 

  143. Doyle, E., Nolan, P. M., Bell, R. & Regan, C. M. Intraventricular infusions of anti-neural cell adhesion molecules in a discrete posttraining period impair consolidation of a passive avoidance response in the rat. J. Neurochem. 59, 1570–1573 (1992).

    Article  CAS  PubMed  Google Scholar 

  144. Futai, K. et al. Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin. Nat. Neurosci. 10, 186–195 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank L. Gabel for helpful comments. The authors work is supported by a Whitehall Foundation, Edward Mallinckrodt Jr Foundation, Philadelphia Foundation, and Mental Retardation Developmental Disability Research Center grant to M.B.D., the Training Program in Developmental Biology to A.C.M. and by the Ruth L. Kirschstein National Research Service Award to M.S.K.

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  1. Department of Neuroscience, University of Pennsylvania Medical Center, BRB II/III, Room 1114, 421 Curie Blvd., Philadelphia, 19104, Pennsylvania, USA

    Matthew B. Dalva, Andrew C. McClelland & Matthew S. Kayser

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FURTHER INFORMATION

Dalva's homepage

Glossary

Synapse formation

The initial contact of two neurons and organization of the earliest components of a young synapse, including presynaptic vesicles and release machinery, and postsynaptic NMDA receptors and PSD-95.

Synaptic plasticity

The ability of certain patterns of activity to lead to increases or decreases in synaptic strength.

Synaptogenesis

The entire process that leads to a fully functional synapse, including cell–cell contact, differentiation of nascent pre- and postsynaptic terminals, development of morphological specializations, and ultimately the organization of mature synaptic inputs.

Alternative splicing

The production of different proteins from the same RNA transcript by combining splice donor and acceptor sites in different combinations.

PDZ binding domain

Protein domains that typically bind specific carboxy-terminal sequences in target proteins. Many proteins contain one or more PDZ domains, which were named after the initial three members (PSD-95, Drosophila discs large protein and ZO-1).

Miniature synaptic current

The postsynaptic current evoked by release of a single vesicle of neurotransmitter — the quantal amplitude.

Synapse maturation

Expansion and stabilization of a synapse characterized by morphological maturation into a mushroom-shaped dendritic spine, additional recruitment of synaptic proteins necessary for plasticity such as AMPA receptors, and other events leading to normal synaptic transmission.

Adaptor protein

A protein that contributes to cellular function by recruiting other proteins to a complex. Such molecules often contain several protein–protein interaction domains.

Yeast two-hybrid screen

System used to determine the existence of direct interactions between proteins. Two hybrid proteins are expressed together in yeast; one is fused to the GAL4 DNA-binding domain and the other is fused to the GAL4 activation domain. If the proteins interact, the resulting complex drives the expression of a reporter gene, commonly β-galactosidase.

Basket cells

Inhibitory interneurons located in the molecular layer of the cerebellum. Basket cells are located close to Purkinje cells and are spread out horizontally.

Active zone

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and neurotransmitter release.

Synaptic vesicle recycling

The process whereby synaptic vesicles release neurotransmitter, are reformed and refilled with neurotransmitter to be re-used in synaptic release.

Long-term potentiation

(LTP). The prolonged strengthening of synaptic inputs, which is induced by patterned input and is thought to be involved in learning and memory formation.

Long-term depression

(LTD). A persistent reduction of synaptic strength in response to weak, poorly correlated input.

Miniature synaptic potentials

Synaptic potentials observed in the absence of presynaptic action potentials; they are thought to correspond to the response elicited by a single vesicle of transmitter.

Morris water maze

A task used to assess spatial memory, most commonly in rodents. Animals use an array of extra-maze cues to locate a hidden escape platform that is submerged below the water surface. Learning in this task is hippocampus-dependent.

Synaptic puncta

The cluster of synaptic proteins labelled with antibodies raised against various synaptic marker proteins.

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Dalva, M., McClelland, A. & Kayser, M. Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci 8, 206–220 (2007). https://doi.org/10.1038/nrn2075

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