Patient‐derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice

Abstract

AbstractThe solute carrier family 6 member 1 (SLC6A1) gene encodes GAT‐1, a γ‐aminobutyric acid transporter expressed on astrocytes and inhibitory neurons. Mutations in SLC6A1 are associated with epilepsy and developmental disorders, including motor and social impairments, but variant‐specific animal models are needed to elucidate mechanisms. Here, we report electrocorticographic (ECoG) recordings and clinical data from a patient with a variant in SLC6A1 that encodes GAT‐1 with a serine‐to‐leucine substitution at amino acid 295 (S295L), who was diagnosed with childhood absence epilepsy. Next, we show that mice bearing the S295L mutation (GAT‐1S295L/+) have spike‐and‐wave discharges with motor arrest consistent with absence‐type seizures, similar to GAT‐1+/− mice. GAT‐1S295L/+ and GAT‐1+/− mice follow the same pattern of pharmacosensitivity, being bidirectionally modulated by ethosuximide (200 mg/kg ip) and the GAT‐1 antagonist NO‐711 (10 mg/kg ip). By contrast, GAT‐1−/− mice were insensitive to both ethosuximide and NO‐711 at the doses tested. In conclusion, ECoG findings in GAT‐1S295L/+ mice phenocopy GAT‐1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations.