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

PLoS Biol. 2021 Jul 6;19(7):e3001323. doi: 10.1371/journal.pbio.3001323. eCollection 2021 Jul.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bipolar Disorder / genetics
  • Bipolar Disorder / metabolism*
  • Calcium / metabolism
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Glutamic Acid / metabolism
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synaptotagmins / genetics
  • Synaptotagmins / physiology*

Substances

  • Receptors, N-Methyl-D-Aspartate
  • Syt7 protein, mouse
  • Synaptotagmins
  • Glutamic Acid
  • Calcium

Grants and funding

This work was supported by National Natural Science Foundation of China (Grant No.31830038, 31771482, 81771466; http://www.nsfc.gov.cn/) and National Key R&D Program of China (Grant No.2016YFA0101900; https://service.most.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.