2. Academic Validation
  3. GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy

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

  • Nat Neurosci. 2025 Jul;28(7):1404-1417. doi: 10.1038/s41593-025-01979-2.
Zhang-Peng Chen # 1 2 3 4 5,  Xiansen Zhao # 1,  Suji Wang # 1,  Ruolan Cai # 6 7,  Qiangqiang Liu 8,  Haojie Ye 1,  Meng-Ju Wang 1,  Shi-Yu Peng 9,  Wei-Xuan Xue 1,  Yang-Xun Zhang 1,  Wei Li 1,  Hua Tang 1,  Tengfei Huang 1,  Qipeng Zhang 1 4,  Liang Li 1 4,  Lixia Gao 6 7,  Hong Zhou 10,  Chunhua Hang 11,  Jing-Ning Zhu 1 4,  Xinjian Li 12 13,  Xiangyu Liu 14 15,  Qifei Cong 16 17,  Chao Yan 18 19 20 21 22 23
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
  • 2 Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Epilepsy Center, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
  • 4 Institute for Brain Sciences, Nanjing University, Nanjing, China.
  • 5 Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China.
  • 6 Department of Neurology of the Second Affiliated Hospital and Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China.
  • 8 Clinical Neuroscience Center, Ruijin Hospital Luwan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 School of Life Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, China.
  • 10 Department of Cell Biology, College of Life Sciences, Anhui Medical University, Hefei, China.
  • 11 Department of Neurosurgery, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
  • 12 Department of Neurology of the Second Affiliated Hospital and Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou, China. lxjbio@zju.edu.cn.
  • 13 MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China. lxjbio@zju.edu.cn.
  • 14 Epilepsy Center, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China. liuxiangyumail@163.com.
  • 15 Department of Neurosurgery, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China. liuxiangyumail@163.com.
  • 16 Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, China. qfcong@suda.edu.cn.
  • 17 Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China. qfcong@suda.edu.cn.
  • 18 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. yanchao@nju.edu.cn.
  • 19 Epilepsy Center, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China. yanchao@nju.edu.cn.
  • 20 Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China. yanchao@nju.edu.cn.
  • 21 Department of Neurosurgery, the Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China. yanchao@nju.edu.cn.
  • 22 Institute of Artificial Intelligence Biomedicine, Nanjing University, Nanjing, China. yanchao@nju.edu.cn.
  • 23 Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, Nanjing, China. yanchao@nju.edu.cn.
  • # Contributed equally.
PMID: 40425792 DOI: 10.1038/s41593-025-01979-2
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.

Figures
Products