Chen Zhang-Peng, Zhao Xiansen, Wang Suji, Cai Ruolan, Liu Qiangqiang, Ye Haojie, Wang Meng-Ju, Peng Shi-Yu, Xue Wei-Xuan, Zhang Yang-Xun, Li Wei, Tang Hua, Huang Tengfei, Zhang Qipeng, Li Liang, Gao Lixia, Zhou Hong, Hang Chunhua, Zhu Jing-Ning, Li Xinjian, Liu Xiangyu, Cong Qifei, Yan Chao
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Neurosci. 2025 May 27. doi: 10.1038/s41593-025-01979-2.
Neuronal hyperexcitability is a common pathophysiological feature of many neurological diseases. Neuron-glia interactions underlie this process but the detailed mechanisms remain unclear. Here, we reveal a critical role of microglia-mediated selective elimination of inhibitory synapses in driving neuronal hyperexcitability. In epileptic mice of both sexes, hyperactive inhibitory neurons directly activate surveilling microglia via GABAergic signaling. In response, these activated microglia preferentially phagocytose inhibitory synapses, disrupting the balance between excitatory and inhibitory synaptic transmission and amplifying network excitability. This feedback mechanism depends on both GABA-GABA receptor-mediated microglial activation and complement C3-C3aR-mediated microglial engulfment of inhibitory synapses, as pharmacological or genetic blockage of both pathways effectively prevents inhibitory synapse loss and ameliorates seizure symptoms in mice. Additionally, putative cell-cell interaction analyses of brain tissues from males and females with temporal lobe epilepsy reveal that inhibitory neurons induce microglial phagocytic states and inhibitory synapse loss. Our findings demonstrate that inhibitory neurons can directly instruct microglial states to control inhibitory synaptic transmission through a feedback mechanism, leading to the development of neuronal hyperexcitability in temporal lobe epilepsy.
神经元过度兴奋是许多神经系统疾病常见的病理生理特征。神经元与神经胶质细胞的相互作用是这一过程的基础，但具体机制仍不清楚。在此，我们揭示了小胶质细胞介导的抑制性突触选择性清除在驱动神经元过度兴奋中起关键作用。在雌雄癫痫小鼠中，过度活跃的抑制性神经元通过GABA能信号直接激活监视小胶质细胞。作为回应，这些被激活的小胶质细胞优先吞噬抑制性突触，破坏兴奋性和抑制性突触传递之间的平衡并增强网络兴奋性。这种反馈机制依赖于GABA-GABA受体介导的小胶质细胞激活和补体C3-C3aR介导的小胶质细胞对抑制性突触的吞噬，因为对这两条途径的药理学或基因阻断都能有效防止抑制性突触丢失并改善小鼠的癫痫症状。此外，对患有颞叶癫痫的雄性和雌性脑组织进行的假定细胞间相互作用分析表明，抑制性神经元会诱导小胶质细胞的吞噬状态和抑制性突触丢失。我们的研究结果表明，抑制性神经元可以通过反馈机制直接指导小胶质细胞状态以控制抑制性突触传递，从而导致颞叶癫痫中神经元过度兴奋的发展。
