Open AccessSynaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants
Author(s) -
Qiu-Wen Wang,
Yinghan Wang,
Bing Wang,
Yun Chen,
Shaoping Lu,
Jun Yao
Publication year - 2021
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001323
Subject(s) - synaptotagmin 1 , biology , exocytosis , syt1 , glutamate receptor , synaptotagmin i , postsynaptic current , postsynaptic potential , microbiology and biotechnology , nmda receptor , neuroscience , synaptic vesicle , endocrinology , biochemistry , receptor , vesicle , gene , peptide sequence , membrane , secretion , hspa2
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.