Cell adhesion molecules: signalling functions at the synapse

Nature Reviews Neuroscience - Tập 8 Số 3 - Trang 206-220 - 2007
Matthew B. Dalva1, Andrew C. McClelland, Matthew S. Kayser
1University of Pennsylvania Medical Center, Department of Neuroscience, BRB II/III, Room 1114, 421 Curie Blvd., Philadelphia, Pennsylvania 19104, USA. [email protected]

Tóm tắt

Từ khóa


Tài liệu tham khảo

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

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

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).

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).

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

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).

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).

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).

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

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).

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).

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).

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

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

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).

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

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

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).

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).

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.

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.

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

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

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).

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).

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

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

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).

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).

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).

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

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.

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).

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).

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).

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

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).

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).

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).

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

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

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

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.

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.

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

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

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.

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).

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).

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).

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

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).

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

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).

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.

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

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

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

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

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

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).

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).

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

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).

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).

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).

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).

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

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

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

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).

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).

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).

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

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

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

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

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

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).

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

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.

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).

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

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

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

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

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

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).

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).

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).

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).

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

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.

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

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).

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).

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.

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).

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).

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).

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

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).

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).

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).

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).

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).

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).

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

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).

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).

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).

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).

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).

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).

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.

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

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).

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).

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).

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).

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).

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).

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).

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).

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).

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).

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.

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

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).

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).

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

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.

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).

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).

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).

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

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).

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).

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).

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).

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).

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).

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).

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