Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.22.109462v1?rss=1 Authors: Wilson, C. S., Dohare, P., Orbeta, S., Ferland, R. J., Sah, R., Scimemi, A., Mongin, A. A. Abstract: The leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is indispensable for cell volume regulation but its broader physiological functions remain a matter of investigation. Astrocyte-targeted Lrrc8a deletion in the nervous system reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against ischemic damage. Here we show that deletion of LRRC8A in all brain cells, using NestinCre -driven Lrrc8afl/fl excision, is lethal. Mice devoid of brain LRRC8A are born close to the expected Mendelian ratio and develop without overt histological abnormalities through the postnatal week 6. Nevertheless, they die in the adolescence, between 5 to 8 weeks of age, with a seizure-like phenotype. Consistent with seizures, we found disruptions in cell excitability, GABAergic signaling, and astrocytic production of the GABA precursor glutamine, all of which might contribute to animal mortality. This work provides the first evidence of a critical role for VRAC in control of brain excitability during brain maturation. Copy rights belong to original authors. Visit the link for more info