Language
English
Publication Date
6-22-2026
Journal
JCI Insight
DOI
10.1172/jci.insight.197980
PMID
42325092
PMCID
PMC13313489
PubMedCentral® Posted Date
6-22-2026
PubMedCentral® Full Text Version
Post-print
Abstract
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 KO (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 potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.
Keywords
Animals, Microglia, Male, Phagocytosis, Mice, Seizures, Mice, Knockout, Membrane Proteins, Neuroprotection, Neurons, Kainic Acid, Disease Models, Animal, Immunology, Neuroscience, Epilepsy, Seizures
Published Open-Access
yes
Recommended Citation
Barath, Abhijeet S; Dheer, Aastha; Montier, Laura; et al., "Microglial SWELL1 Deficiency Drives Male-Specific Seizure Vulnerability but Paradoxical Neuroprotection Through Impaired Phagocytosis" (2026). The Brown Foundation: Institute of Molecular Medicine. 144.
https://digitalcommons.library.tmc.edu/molecular_med/144
Graphical Abstract