Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors

Gaga Kochlamazashvili, Oleg Senkov, Sergei Grebenyuk, Catrina Robinson, Mei Fang Xiao, Katharina Stummeyer, Rita Gerardy-Schahn, Andreas K. Engel, Larry Feig, Alexey Semyanov, Vishnu Suppiramaniam, Melitta Schachner, Alexander Dityatev

Research output: Contribution to journalArticle

Abstract

The neural cell adhesion molecule (NCAM) is the predominant carrier of α2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca2+ transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamates cavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1(a mediator of GluN2B signaling top 38 MAPK),or direct inhibition of hyperactive p38MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.

Original languageEnglish (US)
Pages (from-to)4171-4183
Number of pages13
JournalJournal of Neuroscience
Volume30
Issue number11
DOIs
StatePublished - Mar 17 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kochlamazashvili, G., Senkov, O., Grebenyuk, S., Robinson, C., Xiao, M. F., Stummeyer, K., Gerardy-Schahn, R., Engel, A. K., Feig, L., Semyanov, A., Suppiramaniam, V., Schachner, M., & Dityatev, A. (2010). Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors. Journal of Neuroscience, 30(11), 4171-4183. https://doi.org/10.1523/JNEUROSCI.5806-09.2010