In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 7 ( 2021-7-6), p. e3001323-
Abstract:
Synaptotagmin-7 (Syt7) plays direct or redundant Ca 2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca 2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca 2+ dose response and substituting extracellular Ca 2+ with Sr 2+ , we detect that Syt7 directly triggers spontaneous release via its Ca 2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001323
DOI:
10.1371/journal.pbio.3001323.g001
DOI:
10.1371/journal.pbio.3001323.g002
DOI:
10.1371/journal.pbio.3001323.g003
DOI:
10.1371/journal.pbio.3001323.g004
DOI:
10.1371/journal.pbio.3001323.s001
DOI:
10.1371/journal.pbio.3001323.s002
DOI:
10.1371/journal.pbio.3001323.s003
DOI:
10.1371/journal.pbio.3001323.s004
DOI:
10.1371/journal.pbio.3001323.s005
DOI:
10.1371/journal.pbio.3001323.s006
DOI:
10.1371/journal.pbio.3001323.s007
DOI:
10.1371/journal.pbio.3001323.s008
DOI:
10.1371/journal.pbio.3001323.s009
DOI:
10.1371/journal.pbio.3001323.s010
DOI:
10.1371/journal.pbio.3001323.s011
DOI:
10.1371/journal.pbio.3001323.s012
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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