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

The solute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a gamma-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-1(S295L/+) ) have spike-and-wave discharges with motor arrest consistent with absence-type seizures, similar to GAT-1(+/-) mice. GAT-1(S295L/+) 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-1(S295L/+) mice phenocopy GAT-1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations.