Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice
Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice
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DOI：
10.1016/j.bbi.2022.12.019
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发表时间：
2022-12
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通讯作者：
Ji Wang;Hong-Sheng Chen;Hou-Hong Li;Hua Wang;Ruo-Si Zou;Xiaoming Lu;Jie-Xue Wang;Bin-Bin Nie-Bin;Jin-feng Wu;Shuang Li;B. Shan;Peng-Fei Wu;Li‐Hong Long;Zhuang‐li Hu;Jian-Guo Chen;Fang Wang
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作者：
Ji Wang;Hong-Sheng Chen;Hou-Hong Li;Hua Wang;Ruo-Si Zou;Xiaoming Lu;Jie-Xue Wang;Bin-Bin Nie-Bin;Jin-feng Wu;Shuang Li;B. Shan;Peng-Fei Wu;Li‐Hong Long;Zhuang‐li Hu;Jian-Guo Chen;Fang Wang
内侧前额叶皮质(MPFC)的突触丢失与应激相关的情绪障碍有关，如抑郁症。然而，突触消除在抑郁症中的确切作用以及它是如何被触发的，在很大程度上还不清楚。通过对活体脑内mPFC的重复纵向成像，我们发现慢性应激时mPFC突触前和突触后成分均下降，突触重构和跨突触信号传递受损。同时，慢性应激还导致小胶质细胞过度吞噬，导致兴奋性突触被吞噬。进一步的研究发现，在应激过程中升高的补体C3作为突触的标签被小胶质细胞消除。此外，慢性应激导致mPFC与邻近区域之间的连通性降低。C3基因敲除小鼠表现出突触修剪的显著减少和mPFC功能连接中断的缓解，从而对慢性应激具有更强的弹性。这些结果表明，成年期补体介导的过度小胶质细胞吞噬导致突触功能障碍和皮质连接不足，导致应激相关的行为异常。
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.