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

• Published in: Frontiers in cellular neuroscience Vol. 17; p. 1175895
• Main Authors: Colombo, Sophie, Reddy, Haritha P, Petri, Sabrina, Williams, Damian J, Shalomov, Boris, Dhindsa, Ryan S, Gelfman, Sahar, Krizay, Daniel, Bera, Amal K, Yang, Mu, Peng, Yueqing, Makinson, Christopher D, Boland, Michael J, Frankel, Wayne N, Goldstein, David B, Dascal, Nathan
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 18.05.2023; Frontiers Media S.A
• Subjects: animal model; Antiepileptic agents; Calcium channels; Calcium channels (T-type); Calcium channels (voltage-gated); Cellular Neuroscience; Channel gating; Convulsions & seizures; Encephalopathy; Epilepsy; Experiments; Firing pattern; G protein; GIRK; GNB1; Laboratory animals; Mutation; Neural networks; neurodevelopmental disorder; Neurodevelopmental disorders; Oocytes; Physiology; Potassium; Potassium channels (inwardly-rectifying); Potassium channels (voltage-gated); Proteins; Seizures; spike-wave discharges; neurodevelopmental disorder; spike-wave discharges; GNB1; GIRK; animal model; absence seizures; G protein; ethosuximide
• ISSN: 1662-5102; 1662-5102
• DOI: 10.3389/fncel.2023.1175895

mutations in , encoding the G subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy, 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 and suppresses spike-and-wave discharges (SWD) . ETX is a known blocker of T-type voltage-gated Ca channels and G protein-coupled potassium (GIRK) channels. Accordingly, we present evidence that K78R results in a gain-of-function (GoF) effect by increasing the activation of GIRK channels in cultured neurons and a heterologous model ( oocytes)-an effect we show can be potently inhibited by ETX. This work implicates a GoF mechanism for GIRK channels in epilepsy, identifies a new mechanism of action for ETX in preventing seizures, and establishes this mouse model as a pre-clinical tool for translational research with predicative value for encephalopathy.