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

Zavalin, K.; Randhave, K.; Biven, M.; Shen, W.; Kang, J.-Q.

doi:10.64898/2026.01.20.700615

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bioRxiv · 10.64898/2026.01.20.700615

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

Zavalin, K.·Randhave, K.·Biven, M.·Shen, W.·Kang, J.-Q.

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Abstract

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.

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Zavalin, K., Randhave, K., Biven, M., Shen, W., Kang, J.-Q.. 2026-01-21. Accumulation of Extracellular GABA, Impaired GABAergic Neurotransmission and 4-Phenylbutyrate Rescue in Mice of SLC6A1 Variant-Mediated Disorders. https://doi.org/10.64898/2026.01.20.700615

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