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

Autor: Lindquist BE; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.; Department of Neurology, University of California, San Francisco, Weill Institute, San Francisco, California, USA., Voskobiynyk Y; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.; Department of Neurology, University of California, San Francisco, Weill Institute, San Francisco, California, USA., Goodspeed K; University of Texas Southwestern Medical Center, Dallas, California, USA., Paz JT; Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, California, USA.; Department of Neurology, University of California, San Francisco, Weill Institute, San Francisco, California, USA.; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California, USA.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2023 Oct; Vol. 64 (10), pp. e214-e221. Date of Electronic Publication: 2023 Aug 08.
DOI: 10.1111/epi.17731
Abstrakt: The 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-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.
(© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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