Satellite microglia gate neuronal excitability by shielding inhibitory synapses in adult brain

Zhao, S.; Fei, M.; Zheng, J.; Christensen, T. A.; Kleidonas, D.; Liang, Y.; Qi, F.; Haruwaka, K.; Wang, L.; Worrell, G. A.; Nguyen, A. T.; Wu, L.-J.

doi:10.64898/2025.12.13.694073

bioRxiv · 10.64898/2025.12.13.694073

Satellite microglia gate neuronal excitability by shielding inhibitory synapses in adult brain

Zhao, S.·Fei, M.·Zheng, J.·Christensen, T. A.·Kleidonas, D.·Liang, Y.·Qi, F.·Haruwaka, K.·Wang, L.·Worrell, G. A.·Nguyen, A. T.·Wu, L.-J.

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Abstract

Microglia, the primary immune cells of the central nervous system, are known for sculpting excitatory neural circuits via dynamic processes. However, their role in modulating inhibitory synaptic connections in adulthood remains largely unexplored. In this study, we identified an underappreciated microglia subpopulation, satellite microglia with physical soma-soma contact with neurons, that reshape inhibitory circuit connectivity and gate neuronal activity by shielding inhibitory synapses in the adult mouse brain. Using chronic in vivo two-photon imaging in adult mice, we observed in real time that satellite microglia associations displaced perisomatic inhibitory synapses whereas their dissociation permitted inhibitory synaptogenesis. Redistribution of satellite microglia reorganized inhibitory connectivity, altered local neural networks and changed behaviors. These findings establish satellite microglia as key architects of inhibitory circuitry and suggest their broader role in neural plasticity in health and disease.

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Zhao, S., Fei, M., Zheng, J., Christensen, T. A., Kleidonas, D., Liang, Y., Qi, F., Haruwaka, K., Wang, L., Worrell, G. A., Nguyen, A. T., Wu, L.-J.. 2025-12-14. Satellite microglia gate neuronal excitability by shielding inhibitory synapses in adult brain. https://doi.org/10.64898/2025.12.13.694073

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