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Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice.

. 2020 Feb 25;117(8):4392-4399. Epub 2020 Feb 10
Wei Shen 1 , Qiu-Wen Wang 1 , Yao-Nan Liu 1 , Maria C Marchetto 2 , Sara Linker 2 , Si-Yao Lu 1 , Yun Chen 1 , Chuihong Liu 3 , Chongye Guo 4 , Zhikai Xing 4 , Wei Shi 5 , John R Kelsoe 6 , Martin Alda 7 , Hongwei Wang 8 , Yi Zhong 9 , Sen-Fang Sui 10 , Mei Zhao 11 , Yiming Yang 12 , Shuangli Mi 4 , Liping Cao 3 , Fred H Gage 13 , Jun Yao 14
Wei Shen 1 , Qiu-Wen Wang 1 , Yao-Nan Liu 1 , Maria C Marchetto 2 , Sara Linker 2 , Si-Yao Lu 1 , Yun Chen 1 , Chuihong Liu 3 , Chongye Guo 4 , Zhikai Xing 4 , Wei Shi 5 , John R Kelsoe 6 , Martin Alda 7 , Hongwei Wang 8 , Yi Zhong 9 , Sen-Fang Sui 10 , Mei Zhao 11 , Yiming Yang 12 , Shuangli Mi 4 , Liping Cao 3 , Fred H Gage 13 , Jun Yao 14
+ et al

[No authors listed]

Author information
  • 1 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 2 Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
  • 3 Guangzhou Huiai Hospital, Affiliated Brain Hospital of Guangzhou Medical University, 510370 Guangzhou, Guangdong, China.
  • 4 University of Chinese Academy of Sciences, 100049 Beijing, China.
  • 5 Beijing Advanced Innovation Center for Big Data-based Precision Medicine, Beihang University, 100191 Beijing, China.
  • 6 Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093.
  • 7 Department of Psychiatry, Dalhousie University, Halifax, NS B3H 2E2, Canada.
  • 8 Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 9 Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, 100084, Beijing, China.
  • 10 State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, 100084 Beijing, China.
  • 11 University of Chinese Academy of Sciences, 101408 Beijing, China.
  • 12 School of Linguistic Sciences and Arts, Collaborative Innovation Center for Language Ability, Jiangsu Normal University, 221009 Xuzhou, Jiangsu, China.
  • 13 Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037; gage@salk.edu jyao@mail.tsinghua.edu.cn.
  • 14 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, 100084 Beijing, China; gage@salk.edu jyao@mail.tsinghua.edu.cn.

摘要


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.

KEYWORDS: bipolar disorder, induced pluripotent stem cell, mental disorder, synaptotagmin-7