Same Channel, Different Tune.

Abstract

Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood EpilepsyShore AN, Colombo S, Tobin WF, et al. Cell Rep. 2020;33(4):108303.doi:10.1016/j.celrep.2020.108303Gain-of-function (GOF) variants in K+ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K+ currents lead to network hyperexcitability. Here, we introduce a human Na+-activated K+ (KNa) channel variant (KCNT1-Y796H) into mice, and using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases KNa currents in cortical excitatory and inhibitory neurons, there is an increase in the KNa current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory neuron-specific impairments in excitability and action potential generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell type–specific currents and effects as promising targets for therapeutic intervention.