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Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice
Shen, Wei1; Wang, Qiu-Wen1; Liu, Yao-Nan1; Marchetto, Maria C.2; Linker, Sara2; Lu, Si-Yao1; Chen, Yun1; Liu, Chuihong3; Guo, Chongye4,5; Xing, Zhikai4,5; Shi, Wei6; Kelsoe, John R.7; Alda, Martin8; Wang, Hongwei9; Zhong, Yi10; Sui, Sen-Fang11; Zhao, Mei12,13; Yang, Yiming14; Mi, Shuangli4,5; Cao, Liping3; Gage, Fred H.2; Yao, Jun1
First AuthorShen, Wei
2020-02-25
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN0027-8424
Subtypearticle
Volume117Issue:8Pages:4392-4399
Abstract

The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.

Keywordsynaptotagmin-7 induced pluripotent stem cell mental disorder bipolar disorder
DOI10.1073/pnas.1918165117
Indexed BySCI
Language英语
Funding OrganizationNational Key R&D Program of China ; National Natural Science Foundation of China ; Beijing Municipal Science & Technology Commission ; Open Project of State Key Laboratory of Membrane Biology ; National Institutes of Health ; JPB Foundation ; Leona M. and Harry B. Helmsley Charitable Trust ; Annette Merle-Smith ; Mathers Foundation
Funding ProjectNational Key R&D Program of China[2016YFA0101900] ; National Natural Science Foundation of China[31830038] ; National Natural Science Foundation of China[31771482] ; National Natural Science Foundation of China[81771466] ; Beijing Municipal Science & Technology Commission[Z181100001518001] ; Open Project of State Key Laboratory of Membrane Biology ; National Institutes of Health[U19MH106434] ; National Institutes of Health[U01MH106882] ; JPB Foundation ; Leona M. and Harry B. Helmsley Charitable Trust ; Annette Merle-Smith ; Mathers Foundation
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000516771500066
PublisherNATL ACAD SCIENCES
WOS KeywordINSULIN-SECRETION ; ANIMAL-MODELS ; DISORDER ; MANIA ; SCHIZOPHRENIA ; DEPRESSION ; GLUCOSE
Citation statistics
Document Type期刊论文
Identifierhttp://ir.psych.ac.cn/handle/311026/30945
Collection中国科学院心理健康重点实验室
Corresponding AuthorGage, Fred H.; Yao, Jun
Affiliation1.Tsinghua Univ, IDG McGovern Inst Brain Res, State Key Lab Membrane Biol, Tsinghua Peking Ctr Life Sci,Sch Life Sci, Beijing 100084, Peoples R China
2.Salk Inst Biol Studies, Lab Genet, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA
3.Guangzhou Med Univ, Affiliated Brain Hosp, Guangzhou Huiai Hosp, Guangzhou 510370, Guangdong, Peoples R China
4.Chinese Acad Sci, Beijing Inst Genom, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Beihang Univ, Beijing Adv Innovat Ctr Big Data Based Precis Med, Beijing 100191, Peoples R China
7.Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA
8.Dalhousie Univ, Dept Psychiat, Halifax, NS B3H 2E2, Canada
9.Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China
10.Tsinghua Univ, IDG McGovern Inst Brain Res, Sch Life Sci, Tsinghua Peking Ctr Life Sci, Beijing 100084, Peoples R China
11.Tsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China
12.Chinese Acad Sci, Inst Psychol, Key Lab Mental Hlth, Beijing 100101, Peoples R China
13.Univ Chinese Acad Sci, Beijing 101408, Peoples R China
14.Jiangsu Normal Univ, Collaborat Innovat Ctr Language Abil, Sch Linguist Sci & Arts, Xuzhou 221009, Jiangsu, Peoples R China
Recommended Citation
GB/T 7714
Shen, Wei,Wang, Qiu-Wen,Liu, Yao-Nan,et al. Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2020,117(8):4392-4399.
APA Shen, Wei.,Wang, Qiu-Wen.,Liu, Yao-Nan.,Marchetto, Maria C..,Linker, Sara.,...&Yao, Jun.(2020).Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,117(8),4392-4399.
MLA Shen, Wei,et al."Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 117.8(2020):4392-4399.
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