Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission

Yang Chen, Yuhao Gu, Bianbian Wang, Anqi Wei, Nan Dong, Yong Jiang, Xiaoying Liu, Li Zhu, Feng Zhu, Tao Tan, Zexin Jing, Fenghan Mao, Yichi Zhang, Jingyu Yao, Yuxin Yang, Hongyan Wang, Hao Wu, Hua Li, Chaowen Zheng, Xueting Duan, Jingxiao Huo, Xuanang Wu, Shaoqin Hu, Anran Zhao, Ziyang Li, Xu Cheng, Yuhao Qin, Qian Song, Shuqin Zhan, Qiumin Qu, Fanglin Guan (), Huadong Xu (), Xinjiang Kang () and Changhe Wang ()
Additional contact information
Yang Chen: Xi’an Jiaotong University
Yuhao Gu: Xi’an Jiaotong University
Bianbian Wang: Xi’an Jiaotong University
Anqi Wei: Xi’an Jiaotong University
Nan Dong: Xi’an Jiaotong University
Yong Jiang: the Affiliated Hospital of Southwest Medical University
Xiaoying Liu: Xi’an Jiaotong University
Li Zhu: Xi’an Jiaotong University
Feng Zhu: the First Affiliated Hospital of Xi’an Jiaotong University
Tao Tan: Wenzhou Medical University
Zexin Jing: Xi’an Jiaotong University
Fenghan Mao: Xi’an Jiaotong University
Yichi Zhang: Xi’an Jiaotong University
Jingyu Yao: Xi’an Jiaotong University
Yuxin Yang: Xi’an Jiaotong University
Hongyan Wang: Liaocheng University
Hao Wu: Xi’an Jiaotong University
Hua Li: Xi’an Jiaotong University
Chaowen Zheng: Xi’an Jiaotong University
Xueting Duan: Xi’an Jiaotong University
Jingxiao Huo: Xi’an Jiaotong University
Xuanang Wu: Xi’an Jiaotong University
Shaoqin Hu: Xi’an Jiaotong University
Anran Zhao: Xi’an Jiaotong University
Ziyang Li: Xi’an Jiaotong University
Xu Cheng: Southwest Medical University
Yuhao Qin: Southwest Medical University
Qian Song: Xi’an Jiaotong University
Shuqin Zhan: Xi’an Jiaotong University
Qiumin Qu: the First Affiliated Hospital of Xi’an Jiaotong University
Fanglin Guan: Xi’an Jiaotong University
Huadong Xu: Xi’an Jiaotong University
Xinjiang Kang: the Affiliated Hospital of Southwest Medical University
Changhe Wang: Xi’an Jiaotong University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract Schizophrenia is a severe neuropsychiatric disease, but the initiation mechanisms are unclear. Although antipsychotics are effective against positive symptoms, therapeutic interventions for negative symptoms are limited due to the lack of pathophysiological mechanisms. Here we identify synaptotagmin-11 (Syt11) as a potential genetic risk factor and dopamine over-transmission as a mechanism in the development of schizophrenia. Syt11 expression is reduced in individuals with schizophrenia but restored following the treatment with antipsychotics. Syt11 deficiency in dopamine neurons in early adolescence, but not in adults, leads to persistent social deficits and other schizophrenia-like behaviors by mediating dopamine over-transmission in mice. Accordingly, dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits, along with the structural and functional alternations in the mPFC. Notably, local intervention of D2R with clinical drugs presynaptically or postsynaptically exhibits both acute and long-lasting therapeutic effects on social deficits in schizophrenia mice models. These findings not only define Syt11 as a risk factor and DA over-transmission as a potential risk factor initiating schizophrenia, but also propose two D2R-targeting strategies for the comprehensive and long-term recovery of schizophrenia-associated social withdrawal.

Date: 2024
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DOI: 10.1038/s41467-024-54604-4

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