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

Wang Qiu-Wen; Lu Si-Yao; Liu Yao-NanChen YunWei HuiShen WeiChen Yan-FenFu Chong-LeiWang Ying-HanDai AnbangHuang XuanGage Fred H.Xu QiYao Jun

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

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

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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-methylD-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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2020年第49期|31438-31447|共10页
作者
Wang Qiu-Wen; Lu Si-Yao; Liu Yao-NanChen YunWei HuiShen WeiChen Yan-FenFu Chong-LeiWang Ying-HanDai AnbangHuang XuanGage Fred H.Xu QiYao Jun;
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作者单位

State Key Lab Membrane Biol,Tsinghua Univ;

Chinese Acad Med Sci,Chinese Acad Med Sci & Peking Union Med Coll;

Beijing Chao Yang Hosp,Capital Med UnivLab Genet,Salk Inst Biol Studies;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
synaptotagmin 7; mental disorder; bipolar disorder; mania; induced pluripotent stem cell; ASYNCHRONOUS RELEASE; BIPOLAR DISORDER; SYNAPTIC-TRANSMISSION; INSULIN-SECRETION; DEPRESSION; RECEPTOR; KETAMINE; VESICLES; EFFICACY; ISOFORMS;

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

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