Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX, 78229, USA.
Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
Nat Commun. 2024 Nov 12;15(1):9803. doi: 10.1038/s41467-024-54007-5.
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 medial prefrontal cortex (mPFC) in male mice. 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.
空间异质突触损失是许多精神和神经疾病的特征，但潜在机制尚不清楚。在这里，我们发现空间受限的补体激活介导了应激诱导的异质小胶质细胞激活和突触损失，局限于雄性小鼠内侧前额叶皮质（mPFC）的上层。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）的高表达，局限于 mPFC 的上层。缺乏补体成分 C3 的小鼠可免受应激诱导的特定于层的突触损失的影响，并且这些小鼠的 mPFC 中 Apoe 小胶质细胞群体明显减少。此外，C3 基因敲除小鼠也能抵抗应激诱导的快感缺失和工作记忆行为缺陷。我们的研究结果表明，特定于区域的补体和小胶质细胞激活可能导致许多脑部疾病中发现的特定于疾病的空间限制的突触损失和临床症状。
