2026/06/21 by Abhijeet S. Barath, Aastha Dheer, Laura Montier +14 · 1 voice
Neuroscience · Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Neuroinflammation and Neurodegeneration Mechanisms #Adenosine and Purinergic Signaling #Complement system in diseases
paper · doi:10.1172/jci.insight.197980
openalex created_date 2025/10/10 · openalex publication_date 2026/06/21 · openalex updated_date 2026/07/28
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.