Synaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants

Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NM...

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Bibliographic Details
Published in:PLoS biology 2021-07, Vol.19 (7), p.e3001323-e3001323
Main Authors: Wang, Qiu-Wen, Wang, Ying-Han, Wang, Bing, Chen, Yun, Lu, Si-Yao, Yao, Jun
Format: Article
Language:English
Subjects:
Biology and Life Sciences
Bipolar disorder
Calcium (extracellular)
Calcium ions
Cell receptors
CRISPR
Exocytosis
Genes
Genetic aspects
Glutamate receptors
Glutamic acid receptors
Hippocampus
Identification and classification
Inactivation
Ligands
Localization
Medicine and Health Sciences
Membrane proteins
Mental disorders
Methyl aspartate
N-Methyl-D-aspartic acid receptors
Neurons
Properties
Proteins
Quantitative analysis
Sensors
Short Reports
Social Sciences
Synapses
Synaptotagmin
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Summary:Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ 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 Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ 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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3001323