Microglia-Mediated Disinhibition: Taking the Brakes off Epileptic Networks

GABA-Dependent Microglial Elimination of Inhibitory Synapses Underlies Neuronal Hyperexcitability in Epilepsy Chen ZP, Zhao X, Wang S, Cai R, Liu Q, Ye H, Wang MJ, Peng SY, Xue WX, Zhang YX, Li W, Tang H, Huang T, Zhang Q, Li L, Gao L, Zhou H, Hang C, Zhu JN, Li X, Liu X, Cong Q, Yan C. Nat Neurosci . 2025 Jul;28(7):1404–1417. doi: 10.1038/s41593-025-01979-2. Epub 2025 May 27. PMID: 40425792. 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 B 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.