Synaptotagmin IV regulates glial glutamate release

Qi Zhang, Mitsunori Fukuda, Elisabeth Van Bockstaele, Olivier Pascual, Philip G. Haydon

Research output: Contribution to journalArticlepeer-review

161 Citations (Scopus)

Abstract

Calcium-binding synaptotagmins (Syts) are membrane proteins that are conserved from nematode to human. Fifteen Syts (Syts I-XV) have been identified in mammalian species. Syt I has been well studied and is a candidate for the Ca2+-sensor that triggers evoked exocytosis underlying fast synaptic transmission. Whereas the functions of the other Syts are unclear, Syt IV is of particular interest because it is rapidly up-regulated after chronic depolarization or seizures, and because null mutations exhibit deficits in fine motor coordination and hippocampus-dependent memory. Screening Syts I-XIII, which are enriched in brain, we find that Syt IV is located in processes of astroglia in situ. Reduction of Syt IV in astrocytes by RNA interference decreases Ca2+-dependent glutamate release, a gliotransmission pathway that regulates synaptic transmission. Mutants of the C2B domain, the only putative Ca2+-binding domain in Syt IV, act in a dominant-negative fashion over Ca2+-regulated glial glutamate release, but not gliotransmission induced by changes in osmolarity. Because we find that Syt IV is expressed predominantly by astrocytes and is not in the presynaptic terminals of the hippocampus, and because Syt IV knockout mice exhibit hippocampal-based memory deficits, our data raise the intriguing possibility that Syt IV-mediated gliotransmission contributes to hippocampal-based memory.

Original languageEnglish
Pages (from-to)9441-9446
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number25
DOIs
Publication statusPublished - 2004 Jun 22
Externally publishedYes

ASJC Scopus subject areas

  • General

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