Abhijeet S. Barath, Aastha Dheer, Laura Montier, Mekenzie M Peshoff, Emily C. Dale, Flavia Goche, Thanh Thanh L. Nguyen, Mastura Akter, Fangfang Qi, Dimitrios Kleidonas, Lauren Harris, Sarah A. Jewanee, Anthony D. Umpierre, Dale B. Bosco, Koichiro Haruwaka, Rajan Sah, Long‐Jun Wu
The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type-specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional knockout (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.