Scholarlink

<p>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<sub>B</sub> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2025年5月27日

查看全文
  • Zhang-Peng Chen,
  • Xiansen Zhao,
  • Suji Wang,
  • Ruolan Cai,
  • Qiangqiang Liu,
  • Haojie Ye,
  • Meng-Ju Wang,
  • Shi-Yu Peng,
  • Wei-Xuan Xue,
  • Yang-Xun Zhang,
  • Wei Li,
  • Hua Tang,
  • Tengfei Huang,
  • Qipeng Zhang,
  • Liang Li,
  • Lixia Gao,
  • Hong Zhou,
  • Chunhua Hang,
  • Jing-Ning Zhu,
  • Xinjian Li,
  • Xiangyu Liu,
  • Qifei Cong,
  • Chao Yan

摘要

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.