Complement and microglia activation mediates stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the mouse medial prefrontal cortex (mPFC). Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases. Overall design: Microglia were isolated from cerebral cortices of control/corticosterone treated mice, 4 replicates per treatment, 3-5 mice per replicate空间异质性突触丢失是多种精神疾病与神经系统疾病的典型特征，但其潜在发病机制尚未明确。本研究发现，空间限制性补体激活可介导应激诱导的异质性小胶质细胞活化，以及定位于小鼠内侧前额叶皮层（medial prefrontal cortex, mPFC）上层的突触丢失。单细胞RNA测序结果显示，定位于mPFC上层的应激相关小胶质细胞亚群以载脂蛋白E（apolipoprotein E, APOE）高表达为特征（即Apoehigh小胶质细胞）。补体成分C3缺失的小鼠可免受应激诱导的皮层层特异性突触丢失，且此类小鼠mPFC内的Apoehigh小胶质细胞群体显著减少。此外，C3敲除小鼠还可抵抗应激诱导的快感缺失与工作记忆行为缺陷。本研究结果表明，区域特异性补体与小胶质细胞活化，可能是多种脑部疾病中出现的疾病特异性空间限制性突触丢失模式与临床症状的潜在致病机制。实验整体设计：从对照组与皮质酮处理组小鼠的大脑皮层中分离小胶质细胞，每组设置4个生物学重复，每个重复使用3~5只小鼠。