Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei 430030, China.
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.
Brain Behav Immun. 2023 Mar;109:23-36. doi: 10.1016/j.bbi.2022.12.019. Epub 2022 Dec 27.
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.
内侧前额叶皮层（mPFC）中的突触丢失与应激相关的情绪障碍有关，如抑郁症。然而，在抑郁症中突触消除的确切影响以及它是如何引发的还知之甚少。通过对活体大脑中 mPFC 的重复纵向成像，我们发现慢性应激期间 mPFC 中的突触重塑和交叉突触信号传递受损，同时突触前和突触后成分都下降了。同时，慢性应激还诱导了过度的小胶质细胞吞噬作用，导致兴奋性突触被吞噬。进一步的研究表明，应激期间升高的补体 C3 充当了被小胶质细胞清除的突触标记物。此外，慢性应激导致 mPFC 与相邻区域之间的连接减少。C3 敲除小鼠显示出突触修剪的显著减少和 mPFC 中功能连接的中断得到缓解，从而对慢性应激有更高的抵抗力。这些结果表明，成年期补体介导的过度小胶质细胞吞噬作用导致突触功能障碍和皮质连接减少，从而导致与应激相关的行为异常。
