Complement C1q/C3-CR3 signaling pathway mediates abnormal microglial phagocytosis of synapses in a mouse model of depression.

1. Brain Behav Immun. 2024 Jul;119:454-464. doi: 10.1016/j.bbi.2024.04.018. Epub 2024 Apr 18. Complement C1q/C3-CR3 signaling pathway mediates abnormal microglial phagocytosis of synapses in a mouse model of depression. Han QQ(1), Shen SY(2), Liang LF(3), Chen XR(4), Yu J(5). Author information: (1)Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China. Electronic address: hqq@sumhs.edu.cn. (2)Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Translational Neuroscience, Jing'an District Centre Hospital of Shanghai, Institutes of Brain Science, Fudan University, Shanghai 200032, China. (3)Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China. (4)Department of Physiology, Laboratory of Neurodegenerative Diseases, Changzhi Medical College, Changzhi, Shanxi 046000, China. Electronic address: cxr20020532@126.com. (5)Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai 200433, China. Electronic address: yujin@shmu.edu.cn. BACKGROUND: Both functional brain imaging studies and autopsy reports have indicated the presence of synaptic loss in the brains of depressed patients. The activated microglia may dysfunctionally engulf neuronal synapses, leading to synaptic loss and behavioral impairments in depression. However, the mechanisms of microglial-synaptic interaction under depressive conditions remain unclear. METHODS: We utilized lipopolysaccharide (LPS) to induce a mouse model of depression, examining the effects of LPS on behaviors, synapses, microglia, microglial phagocytosis of synapses, and the C1q/C3-CR3 complement signaling pathway. Additionally, a C1q neutralizing antibody was employed to inhibit the C1q/C3-CR3 signaling pathway and assess its impact on microglial phagocytosis of synapses and behaviors in the mice. RESULTS: LPS administration resulted in depressive and anxiety-like behaviors, synaptic loss, and abnormal microglial phagocytosis of synapses in the hippocampal dentate gyrus (DG) of mice. We found that the C1q/C3-CR3 signaling pathway plays a crucial role in this abnormal microglial activity. Treatment with the C1q neutralizing antibody moderated the C1q/C3-CR3 pathway, leading to a decrease in abnormal microglial phagocytosis, reduced synaptic loss, and improved behavioral impairments in the mice. CONCLUSIONS: The study suggests that the C1q/C3-CR3 complement signaling pathway, which mediates abnormal microglial phagocytosis of synapses, presents a novel potential therapeutic target for depression treatment. Copyright © 2024 Elsevier Inc. All rights reserved. DOI: 10.1016/j.bbi.2024.04.018 PMID: 38642614 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.