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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2024-12-04
DOI
https://doi.org/10.1038/s41467-024-54604-4
Citations
13
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
3.04

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Hua‐Dong Xu, Xinjiang Kang, Xuanang Wu, Anqi Wei et al.
13 citations
Nature Communications
Receptor Mechanisms and Signaling
3.04
article

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

Hua‐Dong Xu, Xinjiang Kang, Xuanang Wu, Anqi Wei, Bianbian Wang, Jingyu Yao, Chaowen Zheng, Changhe Wang, Ziyang Li, Nan Dong, Shuqin Zhan, Tao Tan, Yong Qing Jiang, Fuxiu Mao, Jingxiao Huo, Shaoqin Hu, Fanglin Guan, Hua Li, Yang Chen, Hongyan Wang, Xiaoying Liu, Yichi Zhang, Qian Song, Feng Zhu, Hao Wu, Qiumin Qu, Yuxin Yang, Li Zhu, Xu Cheng, Yuhao Qin, Anran Zhao, Zexin Jing, Xueting Duan, Yanggan Gu
article en
13 citations

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.

Nature CommunicationsVol. 15(1)
Liaocheng University (CN), Wenzhou Medical University (CN), Southwest Medical University (CN), Affiliated Hospital of Southwest Medical University (CN), Ministry of Education (IR), First Affiliated Hospital of Xi'an Jiaotong University (CN), Zhejiang Lab (CN), Second Affiliated Hospital of Xi'an Jiaotong University (CN), Heze Municipal Hospital (CN), Jinzhou Kangning Hospital (CN), Xi'an Jiaotong University (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, Natural Science Foundation of Shaanxi Province, Fourth Military Medical University, Peking University, Directorate for Biological Sciences
Reduced inequalities
Openalex Percentile: Top 8%
Receptor Mechanisms and Signaling
3.04
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.