TY - JOUR
T1 - Neurons Are GIRKed in GNB1 Encephalopathy
T2 - Unraveling Pathogenic Mechanisms in a Complex Neurodevelopmental Disorder
AU - Wagnon, Jacy L.
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/11/1
Y1 - 2023/11/1
N2 - Epilepsy in a Mouse Model of GNB1 Encephalopathy Arises From Altered Potassium (GIRK) Channel Signaling and Is Alleviated by a GIRK Inhibitor Colombo A, Reddy HP, Petri S, Williams DJ, Shalomov B, Dhindsa RS, Gelfman S, Krizay D, Bera AK, Yang M, Peng Y, Makinson CD, Boland MJ, Frankel WN, Goldstein DB, Dascal N. Front Cell Neurosci. 2023;17:1175895. doi:10.3389/fncel.2023.1175895 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.
AB - Epilepsy in a Mouse Model of GNB1 Encephalopathy Arises From Altered Potassium (GIRK) Channel Signaling and Is Alleviated by a GIRK Inhibitor Colombo A, Reddy HP, Petri S, Williams DJ, Shalomov B, Dhindsa RS, Gelfman S, Krizay D, Bera AK, Yang M, Peng Y, Makinson CD, Boland MJ, Frankel WN, Goldstein DB, Dascal N. Front Cell Neurosci. 2023;17:1175895. doi:10.3389/fncel.2023.1175895 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.
UR - http://www.scopus.com/inward/record.url?scp=85178201690&partnerID=8YFLogxK
U2 - 10.1177/15357597231202859
DO - 10.1177/15357597231202859
M3 - Comment/debate
AN - SCOPUS:85178201690
SN - 1535-7597
VL - 23
SP - 381
EP - 382
JO - Epilepsy Currents
JF - Epilepsy Currents
IS - 6
ER -