Journal
JOURNAL OF CELL BIOLOGY
Volume 174, Issue 7, Pages 1071-1085Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200604145
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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 (CaMKII alpha) 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 CaMKII alpha. Degeneration of the spectrin scaffold in NCAM-deficient neurons results in an inability to recruit CaMKII alpha 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.
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