GIRK Channel Loss of Function Increases Dendritic Excitability in a Mouse Model of GNB1 Encephalopathy

Abstract

GNB1 encephalopathy (GNB1-E) is a rare neurodevelopmental disorder associated with motor dysfunction, epilepsy and learning disability caused by mutations in the gene encoding the G protein subunit G{beta}1. Previous work has shown that altered G{beta}1 can disrupt activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels, dysregulate neuronal excitability and cause seizures. However, the relevant upstream regulators of G{beta}1 and the consequences of GIRK dysfunction for neuronal synaptic, cellular and circuit function have not been characterized. Here we report that mice of both sexes carrying the deleterious p.I80T mutation in Gnb1 present features consistent with GNB1-E, including developmental delay, decreased locomotion and increased anxiety. Using histology, whole-cell patch-clamp electrophysiology and pharmacology in ex vivo brain slices, we find that hippocampal neurons in heterozygous Gnb1I80T/+ mice exhibit simplified dendritic morphologies, decreased synaptic inhibition mediated by metabotropic GABAB receptors and increased dendritic excitability. These phenotypes result in longer duration dendritic calcium spikes in response to synaptic afferent stimulation, an effect that is reversed by a specific activator of GIRK channels, ML297. Given the known roles of dendritic calcium spikes in driving burst firing and inducing synaptic plasticity, these findings suggest that targeting dendritic excitability has therapeutic potential to address both the seizure susceptibility and learning deficits associated with GNB1-E. Significance StatementGNB1 encephalopathy (GNB1-E) is a rare neurodevelopmental disorder associated with motor dysfunction, epilepsy and learning disability for which there are currently no mechanism-based treatments. Here we show that a pathogenic variant of the G protein subunit G{beta}1 impairs activation of neuronal G-protein-coupled inwardly rectifying potassium (GIRK) channels by inhibitory synaptic GABAB receptors. This leads to increased dendritic excitability and longer duration dendritic calcium spikes in mouse hippocampal neurons in response to stimulation of synaptic inputs. We find that this phenotype is reversed by a drug that activates GIRK channels, opening pathways to develop therapies for GNB1-E that specifically target dendritic excitability.