Soteros Breeanne M, Tillmon Haven, Wollet Mackenna, General Julianne, Chin Hanna, Lee John Beichen, Carreno Flavia R, Morilak David A, Kim Jun Hee, Sia Gek Ming
bioRxiv. 2023 Sep 14:2023.06.28.546889. doi: 10.1101/2023.06.28.546889.
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 (ApoE ) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the ApoE 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.
空间异质性突触丢失是许多精神和神经疾病的一个特征，但潜在机制尚不清楚。在这里，我们表明空间受限的补体激活介导了应激诱导的异质性小胶质细胞激活以及定位于小鼠内侧前额叶皮质（mPFC）上层的突触丢失。单细胞RNA测序还揭示了一种与应激相关的小胶质细胞状态，其特征是载脂蛋白E基因（ApoE）在mPFC上层高表达。缺乏补体成分C3的小鼠可免受应激诱导的层特异性突触丢失的影响，并且这些小鼠的mPFC中ApoE小胶质细胞群体明显减少。此外，C3基因敲除小鼠对应激诱导的快感缺失和工作记忆行为缺陷也具有抵抗力。我们的研究结果表明，区域特异性补体和小胶质细胞激活可能导致许多脑部疾病中发现的疾病特异性空间受限的突触丢失模式和临床症状。
