A Role for the Cadherin Family of Cell Adhesion Molecules in Hippocampal Long-Term Potentiation

The cadherins are a family of cell-cell adhesion molecules that mediate Ca2+-dependent homophilic interactions between cells and transduce signals by interacting with cytoplasmic proteins. In the hippocampus, immunostaining combined with confocal microscopy revealed that both neural- (N-) and epithelial- (E-) cadherin are present at synaptic sites, implying a role in synaptic function. Pretreatment of hippocampal slices with antibodies (Abs) raised against the extracellular domain of either N-cad or E-cad had no effect on basal synaptic properties but significantly reduced long-term potentiation (LTP). Infusion of antagonistic peptides containing the His-Ala-Val (HAV) consensus sequence for cadherin dimerization also attenuated LTP induction without affecting previously established LTP. Because the intense synaptic stimulation associated with LTP induction might transiently deplete extracellular Ca2+ and hence potentially destabilize cadherin-cadherin interactions, we examined whether slices could be protected from inhibition by N-cad Abs or HAV peptides by raising the extracellular Ca2+ concentration. Indeed, we found that high extracellular Ca2+ prevented the block of LTP by these agents. Taken together, these results indicate that cadherins are involved in synaptic plasticity, and the stability of cadherin-cadherin bonds may be regulated by synaptic stimulation.

[1]  C. Holt,et al.  Cadherin Function Is Required for Axon Outgrowth in Retinal Ganglion Cells In Vivo , 1996, Neuron.

[2]  A. Lustig,et al.  Calcium binding and homoassociation of E-cadherin domains. , 1997, Biochemistry.

[3]  D. Colman.  Neurites, Synapses, and Cadherins Reconciled , 1997, Molecular and Cellular Neuroscience.

[4]  A. Lüthi,et al.  Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM , 1994, Nature.

[5]  M. Perricaudet,et al.  Transfer of a foreign gene into the brain using adenovirus vectors , 1993, Nature Genetics.

[6]  G. Lynch,et al.  Evidence that matrix recognition contributes to stabilization but not induction of LTP. , 1991, Neuroreport.

[7]  E. Litwack,et al.  Neuronal expression of glypican, a cell-surface glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan, in the adult rat nervous system , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[8]  R. U. Margolis,et al.  Immunocytochemical and in situ hybridization studies of the heparan sulfate proteoglycan, glypican, in nervous tissue. , 1994, Journal of cell science.

[9]  A. Grinnell,et al.  Integrins and modulation of transmitter release from motor nerve terminals by stretch. , 1995, Science.

[10]  G. Lynch,et al.  Arg-Gly-Asp-Ser-Selective Adhesion and the Stabilization of Long-Term Potentiation: Pharmacological Studies and the Characterization of a Candidate Matrix Receptor , 1997, The Journal of Neuroscience.

[11]  N. Toni,et al.  PSA–NCAM Is Required for Activity-Induced Synaptic Plasticity , 1996, Neuron.

[12]  G. Edelman,et al.  Allosteric modulation of AMPA-type glutamate receptors increases activity of the promoter for the neural cell adhesion molecule, N-CAM. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Kristen M. Harris,et al.  Quantal analysis and synaptic anatomy — integrating two views of hippocampal plasticity , 1993, Trends in Neurosciences.

[14]  T. Serafini.  An old friend in a new home: cadherins at the synapse. , 1997, Trends in neurosciences.

[15]  H Weissig,et al.  Assembly of the cadherin-catenin complex in vitro with recombinant proteins. , 1994, Journal of cell science.

[16]  J. Revel,et al.  Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies , 1992, The Journal of cell biology.

[17]  F. Walsh,et al.  Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin , 1994, Neuron.

[18]  C. Siu,et al.  The Neural Cell Adhesion Molecule NCAM , 1995 .

[19]  G. Lynch,et al.  An inhibitor of integrin receptors blocks long-term potentiation. , 1990, Behavioral and neural biology.

[20]  K. Krnjević,et al.  Stimulation-evoked changes in extracellular K+ and Ca2+ in pyramidal layers of the rat's hippocampus. , 1982, Canadian journal of physiology and pharmacology.

[21]  R. Mummery,et al.  N‐Cadherin Is a Major Glycoprotein Component of Isolated Rat Forebrain Postsynaptic Densities , 1995, Journal of neurochemistry.

[22]  E. Schuman,et al.  Neurotrophins and Time: Different Roles for TrkB Signaling in Hippocampal Long-Term Potentiation , 1997, Neuron.

[23]  A. Magee,et al.  Structure and interactions of desmosomal and other cadherins. , 1992, Seminars in cell biology.

[24]  B. Geiger,et al.  Cleavage of A-CAM by endogenous proteinases in cultured lens cells and in developing chick embryos. , 1990, Developmental biology.

[25]  M. Takeichi,et al.  The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones , 1996, The Journal of cell biology.

[26]  C. Nicholson,et al.  Calcium and potassium changes in extracellular microenvironment of cat cerebellar cortex. , 1978, Journal of neurophysiology.

[27]  G. Lynch,et al.  Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. , 1986, Science.

[28]  J R Sanes,et al.  Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates. , 1997, Science.

[29]  O. Blaschuk,et al.  Identification of a cadherin cell adhesion recognition sequence. , 1990, Developmental biology.

[30]  M. Yamagata,et al.  Lamina-specific expression of adhesion molecules in developing chick optic tectum , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  R. Fields,et al.  Activity-dependent regulation of N-cadherin in DRG neurons: differential regulation of N-cadherin, NCAM, and L1 by distinct patterns of action potentials. , 1997, Journal of neurobiology.

[32]  O. Blaschuk,et al.  Differentiation and survival of rat olfactory epithelial neurons in dissociated cell culture. , 1991, Brain research. Developmental brain research.

[33]  D. Colman,et al.  A Model for Central Synaptic Junctional Complex Formation Based on the Differential Adhesive Specificities of the Cadherins , 1996, Neuron.

[34]  M. Nicolet,et al.  N-cadherin and N-CAM in myoblast fusion: compared localisation and effect of blockade by peptides and antibodies. , 1992, Journal of cell science.

[35]  N. Nishiyama,et al.  Effects of acidic fibroblast growth factor on higpocampal long‐term potentiation in fasted rats , 1992, Journal of neuroscience research.

[36]  M. Takeichi.  Morphogenetic roles of classic cadherins. , 1995, Current opinion in cell biology.

[37]  J. Engel,et al.  Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding. , 1994, European journal of biochemistry.

[38]  F. Walsh,et al.  Neurite outgrowth in response to transfected N-CAM and N-cadherin reveals fundamental differences in neuronal responsiveness to CAMs , 1991, Neuron.

[39]  R. Fields,et al.  Regulated Expression of the Neural Cell Adhesion Molecule L1 by Specific Patterns of Neural Impulses , 1995, Science.

[40]  T. Yoneda,et al.  The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow. , 1995, The Journal of clinical investigation.

[41]  E R Kandel,et al.  Serotonin-mediated endocytosis of apCAM: an early step of learning-related synaptic growth in Aplysia. , 1992, Science.

[42]  Akinao Nose,et al.  Localization of specificity determining sites in cadherin cell adhesion molecules , 1990, Cell.

[43]  Peter D. Kwong,et al.  Structural basis of cell-cell adhesion by cadherins , 1995, Nature.

[44]  M. Mareel,et al.  Cadherin‐dependent cell aggregation is affected by decapeptide derived from rat extracellular super‐oxide dismutase , 1995, FEBS letters.

[45]  W. Nelson,et al.  Genetic and biochemical dissection of protein linkages in the cadherin-catenin complex. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. Bliss,et al.  Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1 , 1996, Nature.

[47]  E. Kandel,et al.  Modulation of an NCAM-related adhesion molecule with long-term synaptic plasticity in Aplysia. , 1992, Science.

[48]  F. Jacob,et al.  Cell-cell interactions in early embryogenesis: A molecular approach to the role of calcium , 1981, Cell.

[49]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[50]  P. Bjorkman,et al.  The (Greek) Key to Structures of Neural Adhesion Molecules , 1996, Neuron.

[51]  B. Gustafsson,et al.  Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.