Accumulation of Extracellular GABA, Impaired GABAergic Neurotransmission and 4-Phenylbutyrate Rescue in Mice of SLC6A1 Variant-Mediated Disorders

Mutations in SLC6A1 encoding GABA transporter 1 are a leading monogenic cause of developmental and epileptic encephalopathies, severe neurodevelopmental disorders lacking effective treatments. We previously demonstrated that 4-phenylbutyrate restored molecular and functional deficits, and reduced seizures in a Slc6a1 loss-of-function mouse, motivating a promising ongoing clinical trial. Here, we show this mouse exhibits accumulation of extracellular GABA, impaired neurotransmission, and reduced GABA uptake; and demonstrate that 4-phenylbutyrate rescues these abnormalities.