NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex.
The neural cell adhesion molecule (NCAM) regulates synapse formation and synaptic strength via mechanisms that have remained unknown. We show that NCAM associates with the postsynaptic spectrin-based scaffold, cross-linking NCAM with the N-methyl-d-aspartate (NMDA) receptor and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIalpha) in a manner not firmly or directly linked to PSD95 and alpha-actinin. Clustering of NCAM promotes formation of detergent-insoluble complexes enriched in postsynaptic proteins and resembling postsynaptic densities. Disruption of the NCAM-spectrin complex decreases the size of postsynaptic densities and reduces synaptic targeting of NCAM-spectrin-associated postsynaptic proteins, including spectrin, NMDA receptors, and CaMKIIalpha. Degeneration of the spectrin scaffold in NCAM-deficient neurons results in an inability to recruit CaMKIIalpha to synapses after NMDA receptor activation, which is a critical process in NMDA receptor-dependent long-term potentiation. The combined observations indicate that NCAM promotes assembly of the spectrin-based postsynaptic signaling complex, which is required for activity-associated, long-lasting changes in synaptic strength. Its abnormal function may contribute to the etiology of neuropsychiatric disorders associated with mutations in or abnormal expression of NCAM.
Sytnyk
Vladimir
V
Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany.
Leshchyns'ka
Iryna
I
Nikonenko
Alexander G
AG
Schachner
Melitta
M
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D019006:Neural Cell Adhesion Molecules / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013049:Spectrin / Q000502:physiology
D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D013049:Spectrin; D017871:Calcium-Calmodulin-Dependent Protein Kinases