Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons

Abstract

SUMMARYKCNT1encodes the sodium-activated potassium channel Slack (KCNT1, KNa1.1), an important mediator of neuronal membrane excitability. Gain-of-function (GOF) mutations in humans lead cortical network hyperexcitability and seizures, as well as very severe intellectual disability. Using a mouse model of Slack GOF-associated epilepsy, we found that both excitatory and inhibitory neurons of the cerebral cortex have increased Na+-dependent K+(KNa) currents and voltage-dependent sodium (NaV) currents. The characteristics of the increased KNacurrents were, however, different in the two cell types such that the intrinsic excitability of excitatory neurons was enhanced but that of inhibitory neurons was suppressed. We further showed that the expression of NaVchannel subunits, particularly that of NaV1.6, is upregulated and that the length of the axon initial segment (AIS) and of axonal NaVimmunostaining is increased in both neuron types. We found that the proximity of the AIS to the soma is shorter in excitatory neurons than in inhibitory neurons of the mutant animals, potentially contributing to the different effects on membrane excitability. Our study on the coordinate regulation of KNacurrents and the expression of NaVchannels may provide a new avenue for understanding and treating epilepsies and other neurological disorders.In briefIn a genetic mouse model of Na+-activated K+potassium channel geneSlack-related childhood epilepsy, Wuet al. show that a disease-causing gain-of-function (GOF) mutationR455Hin Slack channel causes opposite effects on excitability of cortical excitatory and inhibitory neurons. In contrast to heterologous expression systems, they find that the increase in potassium current substantially alters the expression of sodium channel subunits, resulting in increased lengths of axonal initial segments.HighlightsGOF mutations in Slack potassium channel cause elevated outward K+currents and inward voltage-dependent Na+(NaV) currents in cortical neuronsSlack GOF does not alter the expression of Slack channel but upregulates the expression of NaVchannelSlack GOF enhances the excitability of excitatory neurons but suppresses the firing of inhibitory interneuronsSlack GOF alters the length of AIS in both excitatory and inhibitory neuronsProximity of AIS to the soma is different between excitatory neuron and inhibitory neuron