Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor.

ABSTRACT: De novo mutations in GNB1, encoding the Gβ₁ subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy, GNB1 encephalopathy. Here, we show that mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and generalized seizures. Cultured mutant cortical neurons also display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses spike-and-wave discharges (SWD) in vivo. ETX is a known blocker of T-type voltage-gated Ca²⁺ channels and G protein-coupled potassium (GIRK) channels. Accordingly, we present evidence that K

SUBMITTER: Colombo S 

PROVIDER: S-EPMC10232839 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature