Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice

Ji Wang; Hong-Sheng Chen; Hou-Hong Li; Hua-Jie Wang; Ruo-Si Zou; Xiao-Jia Lu; Jie Wang; Bin-Bin Nie; Jin-Feng Wu; Shuang Li; Bao-Ci Shan; Peng-Fei Wu; Li-Hong Long; Zhuang-Li Hu; Jian-Guo Chen; Fang Wang

doi:10.1016/j.bbi.2022.12.019

Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice

Brain Behav Immun. 2023 Mar:109:23-36. doi: 10.1016/j.bbi.2022.12.019. Epub 2022 Dec 27.

Authors

Ji Wang¹, Hong-Sheng Chen¹, Hou-Hong Li¹, Hua-Jie Wang¹, Ruo-Si Zou¹, Xiao-Jia Lu¹, Jie Wang², Bin-Bin Nie², Jin-Feng Wu², Shuang Li², Bao-Ci Shan², Peng-Fei Wu³, Li-Hong Long³, Zhuang-Li Hu⁴, Jian-Guo Chen⁵, Fang Wang⁶

Affiliations

¹ Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
² State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, 430030 Wuhan, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, 430030 Wuhan, China.
⁴ Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, 430030 Wuhan, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, 430030 Wuhan, China. Electronic address: zlhu916@hust.edu.cn.
⁵ Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, 430030 Wuhan, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, 430030 Wuhan, China. Electronic address: chenj@mail.tjmu.edu.cn.
⁶ Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, 430030 Wuhan, China; Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Wuhan City, Hubei 430030, China; Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, 430030 Wuhan, China. Electronic address: wangfanghust@hust.edu.cn.

PMID: 36581303
DOI: 10.1016/j.bbi.2022.12.019

Abstract

Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality.

Keywords: Complement C3; Microglia; Stress; Synaptic pruning.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Mice
Mice, Knockout
Microglia*
Neuronal Plasticity
Social Defeat*
Synapses