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

Frontiers in Cellular Neuroscience

Cellular Neuroscience

Amal K. Bera¹  Boris Shalomov²  Nathan Dascal²  Haritha P. Reddy³  Ryan S. Dhindsa⁴  Sophie Colombo⁴  Sahar Gelfman⁴  Damian J. Williams⁴  Sabrina Petri⁴  Daniel Krizay⁴  Wayne N. Frankel⁵  David B. Goldstein⁵  Michael J. Boland⁶  Christopher D. Makinson⁷  Yueqing Peng⁸  Mu Yang⁹ 

[1] Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India;Department of Physiology and Pharmacology, School of Medicine, Tel Aviv University, Tel Aviv, Israel;Department of Physiology and Pharmacology, School of Medicine, Tel Aviv University, Tel Aviv, Israel;Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India;Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States;Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States;Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, United States;Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States;Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States;Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States;Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States;Department of Neuroscience, Columbia University, New York, NY, United States;Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States;Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States;Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States;Mouse NeuroBehavior Core Facility, Columbia University Irving Medical Center, New York, NY, United States;

关键词: GNB1;    G protein;    animal model;    neurodevelopmental disorder;    spike-wave discharges;    GIRK;    absence seizures;    ethosuximide;   

DOI  :  10.3389/fncel.2023.1175895

 received in 2023-02-28, accepted in 2023-04-12,  发布年份 2023

来源: Frontiers

【 摘 要 】

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 K78R results in a gain-of-function (GoF) effect by increasing the activation of GIRK channels in cultured neurons and a heterologous model (Xenopus 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 GNB1 encephalopathy.

【 授权许可】

Unknown   
Copyright © 2023 Colombo, Reddy, Petri, Williams, Shalomov, Dhindsa, Gelfman, Krizay, Bera, Yang, Peng, Makinson, Boland, Frankel, Goldstein and Dascal.