Synaptic Strength as a Function of Post- versus Presynaptic Expression of the Neural Cell Adhesion Molecule NCAM

To evaluate the contributions of the pre- versus postsynaptic expression of NCAM in regulation of synaptic efficacy, we cultured dissociated hippocampal cells from NCAM-deficient and wild-type mice in homo- and heterogenotypic combinations. Double recordings from synaptically coupled neurons maintained in heterogenotypic cocultures showed that synaptic strength of excitatory but not inhibitory synapses depended on expression of NCAM post- but not presynaptically. This correlated with higher levels of potentiation and synaptic coverage of NCAM-expressing neurons compared to NCAM-deficient neurons in heterogenotypic cocultures. Synaptic density was the same in homogenotypic cultures of NCAM-deficient and wild-type neurons as well as in heterogenotypic cocultures in which glutamate receptors were blocked. These observations indicate that the relative levels of postsynaptic NCAM expression control synaptic strength in an activity-dependent manner by regulating the number of synapses.

[1]  M. Schachner,et al.  The effect of continuous intraventricular infusion of L1 and NCAM antibodies on spatial learning in rats , 1996, Behavioural Brain Research.

[2]  S. DeKosky,et al.  Regional distribution of neural cell adhesion molecule (N‐CAM) and L1 in human and rodent hippocampus , 1993, The Journal of comparative neurology.

[3]  T. Brümmendorf,et al.  Cell adhesion molecules. 1: immunoglobulin superfamily. , 1994, Protein profile.

[4]  R. Sidman,et al.  Immunoreactive myelin basic proteins are not detected when shiverer mutant Schwann cells and fibroblasts are co-cultured with normal neurons , 1984, The Journal of cell biology.

[5]  K. Rajewsky,et al.  Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning , 1994, Nature.

[6]  M. Schachner,et al.  Expression of L1 and PSA during sprouting and regeneration in the adult hippocampal formation , 1998, The Journal of comparative neurology.

[7]  C. Goodman,et al.  Genetic Analysis of the Mechanisms Controlling Target Selection: Target-Derived Fasciclin II Regulates the Pattern of Synapse Formation , 1997, Neuron.

[8]  T. Bliss,et al.  Increase in extracellular NCAM and amyloid precursor protein following induction of long-term potentiation in the dentate gyrus of anaesthetized rats , 1994, Neuroscience Letters.

[9]  G. Lynch,et al.  Time-Dependent Reversal of Long-Term Potentiation by an Integrin Antagonist , 1998, The Journal of Neuroscience.

[10]  Antonio Malgaroli,et al.  Glutamate-induced long-term potentiation of the frequency of miniature synaptic currents in cultured hippocampal neurons , 1992, Nature.

[11]  M E Hatten,et al.  Motility and cytoskeletal organization of migrating cerebellar granule neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[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]  G. Edelman.  Cell adhesion molecules. , 1983, Science.

[14]  A. Hamberger,et al.  Biphasic changes in NCAM level after an NMDA lesion to the hippocampal formation: A quantitative dot‐immunobinding assay , 1992, Journal of neuroscience research.

[15]  E. Azmitia,et al.  Neuro-glial neurotrophic interaction in the S-100β retarded mutant mouse (Polydactyly Nagoya). II. Co-cultures study , 1994, Brain Research.

[16]  E. Kandel,et al.  Mutation in the Phosphorylation Sites of MAP Kinase Blocks Learning-Related Internalization of apCAM in Aplysia Sensory Neurons , 1997, Neuron.

[17]  A. Carleton,et al.  Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Represa,et al.  NCAM Is Essential for Axonal Growth and Fasciculation in the Hippocampus , 1997, Molecular and Cellular Neuroscience.

[19]  Asla Pitkänen,et al.  Remodeling of neuronal circuitries in human temporal lobe epilepsy: Increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex , 1998, Annals of neurology.

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

[21]  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.

[22]  P. Schulz,et al.  Long-term potentiation involves increases in the probability of neurotransmitter release. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Chou P Hung,et al.  A Role for the Cadherin Family of Cell Adhesion Molecules in Hippocampal Long-Term Potentiation , 1998, Neuron.

[24]  M. Krug,et al.  Increase in proportion of hippocampal spine synapses expressing neural cell adhesion molecule NCAM180 following long-term potentiation. , 1998, Journal of neurobiology.

[25]  M. Schachner,et al.  Immunohistological localization of the neural adhesion molecules L1 and N-CAM in the developing hippocampus of the mouse , 1990, Journal of neurocytology.

[26]  S. Colvin,et al.  Memory and behavior. , 1930 .

[27]  D. Lauffenburger,et al.  Integrin-cytoskeletal interactions in neuronal growth cones , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[28]  M. Schachner,et al.  Transient upregulation of NCAM mRNA in astrocytes in response to entorhinal cortex lesions and ischemia. , 1995, Brain research. Molecular brain research.

[29]  N. Nagai,et al.  Proteolysis of highly polysialylated NCAM by the tissue plasminogen activator-plasmin system in rats , 1998, Neuroscience Letters.

[30]  J. Sanes,et al.  Organization and Reorganization of Neuromuscular Junctions in Mice Lacking Neural Cell Adhesion Molecule, Tenascin-C, or Fibroblast Growth Factor-5 , 1998, The Journal of Neuroscience.

[31]  Richard D Fetter,et al.  Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. II. Fasciclin II Controls Presynaptic Structural Plasticity , 1996, Neuron.

[32]  P. Altevogt,et al.  Functional cooperation between the neural adhesion molecules L1 and N- CAM is carbohydrate dependent , 1990, The Journal of cell biology.

[33]  Richard D Fetter,et al.  Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. I. Fasciclin II Controls Synaptic Stabilization and Growth , 1996, Neuron.

[34]  H. Jahnsen,et al.  NCAM-antibodies modulate induction of long-term potentiation in rat hippocampal CA1 , 1995, Brain Research.

[35]  A. Artola,et al.  The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long‐term potentiation , 1996, Journal of neuroscience research.

[36]  J. Kirsch.  Assembly of signaling machinery at the postsynaptic membrane , 1999, Current Opinion in Neurobiology.

[37]  U. Rutishauser,et al.  Removal of Polysialic Acid–Neural Cell Adhesion Molecule Induces Aberrant Mossy Fiber Innervation and Ectopic Synaptogenesis in the Hippocampus , 1998, The Journal of Neuroscience.

[38]  M. Schachner,et al.  Immunoelectron‐microscopic localization of the 180 kD component of the neural cell adhesion molecule N‐CAM in postsynaptic membranes , 1989, The Journal of comparative neurology.

[39]  P. Altevogt,et al.  The neural cell adhesion molecule N-CAM enhances L1-dependent cell-cell interactions , 1990, The Journal of cell biology.

[40]  C. Goodman,et al.  Synapse-specific control of synaptic efficacy at the terminals of a single neuron , 1998, Nature.

[41]  Robert U Muller,et al.  Memory and behavior: a second generation of genetically modified mice , 1997, Current Biology.

[42]  S. Schacher,et al.  Changes in expression and distribution of Aplysia cell adhesion molecules can influence synapse formation and elimination in vitro , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

[44]  David J. Anderson,et al.  Subregion- and Cell Type–Restricted Gene Knockout in Mouse Brain , 1996, Cell.

[45]  R. Quirion,et al.  Decreased expression of the embryonic form of the neural cell adhesion molecule in schizophrenic brains. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[46]  F. Benfenati,et al.  Molecular and Functional Diversity at Synapses of Individual Neurons In Vitro , 1997, The European journal of neuroscience.

[47]  H. Reuter,et al.  Measurements of exocytosis from single presynaptic nerve terminals reveal heterogeneous inhibition by Ca2+-channel blockers , 1995, Neuron.

[48]  M. Hortsch,et al.  Cis-activation of L1-mediated Ankyrin Recruitment by TAG-1 Homophilic Cell Adhesion* , 1998, The Journal of Biological Chemistry.