Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity

Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31438-31447. doi: 10.1073/pnas.2016416117. Epub 2020 Nov 23.


Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, N-methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.

Keywords: bipolar disorder; induced pluripotent stem cell; mania; mental disorder; synaptotagmin 7.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Behavior, Animal*
  • Bipolar Disorder / genetics
  • Bipolar Disorder / pathology
  • Exocytosis
  • Female
  • Glutamic Acid / metabolism
  • Hippocampus / pathology
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mania / pathology*
  • Mania / physiopathology
  • Mice, Knockout
  • Middle Aged
  • Neurons / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synaptic Vesicles / metabolism
  • Synaptotagmins / deficiency*
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism
  • Young Adult


  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Synaptotagmins
  • Glutamic Acid