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The Journal of Neuroscience, October 20, 2004, 24(42):9372-9382; doi:10.1523/JNEUROSCI.1702-04.2004

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Development/Plasticity/Repair
Polysialylated Neural Cell Adhesion Molecule Promotes Remodeling and Formation of Hippocampal Synapses

Alexander Dityatev,¹ Galina Dityateva,¹ Vladimir Sytnyk,¹ Markus Delling,¹ Nicolas Toni,² Irina Nikonenko,² Dominique Muller,² and Melitta Schachner¹

¹Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany, and ²Department of Basic Neuroscience, University Medical Center, 1211 Geneva 4, Switzerland

Expression of the neural cell adhesion molecule (NCAM) has been shown to promote long-term potentiation (LTP) and stabilization of synapses during early synaptogenesis. Here, we searched for the mechanisms of synaptogenic activity of NCAM, focusing on the role of polysialic acid (PSA), an unusual carbohydrate preferentially associated with NCAM. We show that enzymatic removal of PSA with endoneuraminidase-N (endo-N) abolished preferential formation of synapses on NCAM-expressing cells in heterogenotypic cocultures of wild-type and NCAM-deficient hippocampal neurons. Transfection of NCAM-deficient neurons with either of three major NCAM isoforms (different in intracellular domains but identical in extracellular domains and carrying PSA) stimulated preferential synapse formation on NCAM isoform-expressing neurons. Enzymatic removal of heparan sulfates from cultured neurons and a mutation in the heparin-binding domain of NCAM diminished synaptogenic activity of neuronally expressed PSA-NCAM, suggesting that interaction of NCAM with heparan sulfate proteoglycans mediates this activity. PSA-NCAM-driven synaptogenesis was also blocked by antagonists to fibroblast growth factor receptor and NMDA subtype of glutamate receptors but not by blockers of non-NMDA glutamate receptors and voltage-dependent Na⁺ channels. Enzymatic removal of PSA and heparan sulfates also blocked the increase in the number of perforated spine synapses associated with NMDA receptor-dependent LTP in the CA1 region of organotypic hippocampal cultures. Thus, neuronal PSA-NCAM in complex with heparan sulfate proteoglycans promotes synaptogenesis and activity-dependent remodeling of synapses.

Key words: PSA; NCAM; adhesion; hippocampus; long-term potentiation; perforated synapses; structural plasticity; synaptogenesis

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Received May 4, 2004; revised September 3, 2004; accepted September 4, 2004.

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