Synaptotagmin Ⅳ regulates glial glutamate release

摘要

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 Ca~(2+)-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 Ca~(2+)-dependent glutamate release, a gliotransmission pathway that regulates synaptic transmission. Mutants of the C2B domain, the only putative Ca~(2+)-binding domain in Syt Ⅳ, act in a dominant-negative fashion over Ca~(2+)-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 presyn-aptic 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.