南京大学闫超团队的最新研究探明了GABA依赖性的抑制性突触的小胶质消除是癫痫中神经元高兴奋性的基础。相关论文发表在2025年5月27日出版的《自然—神经科学》杂志上。

研究人员揭示了小胶质细胞介导的选择性消除抑制性突触在驱动神经元高兴奋性中的关键作用。在两性癫痫小鼠中，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，放大网络兴奋性。这种反馈机制依赖于GABA-GABAB受体介导的小胶质细胞激活和补体C3–C3aR介导的小胶质细胞吞噬抑制性突触，因为药物或遗传阻断这两种途径有效地防止抑制性突触丢失并改善小鼠癫痫发作症状。

此外，对颞叶癫痫男性和女性脑组织的细胞相互作用分析表明，抑制性神经元诱导小胶质细胞吞噬状态和抑制性突触丢失。他们的研究结果表明，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控制抑制性突触传递，从而导致颞叶癫痫中神经元高兴奋性的发展。

据了解，神经细胞的高兴奋性是许多神经系统疾病的共同病理生理特征。神经元-神经胶质相互作用是这一过程的基础，但具体机制尚不清楚。

附：英文原文

Title: GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy

Author: 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

Issue&Volume: 2025-05-27

Abstract: 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–GABAB 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.

DOI: 10.1038/s41593-025-01979-2

Source: https://www.nature.com/articles/s41593-025-01979-2