Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons
Jing Wu, Imran H. Quraishi, Yalan Zhang, Mark Bromwich, Leonard K. Kaczmarek
Abstract
The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, K Na 1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause cortical network hyperexcitability, seizures, and severe intellectual disability. Using a mouse model expressing the Slack-R455H mutation, we find that Na + -dependent K + (K Na ) and voltage-dependent sodium (Na V ) currents are increased in both excitatory and inhibitory cortical neurons. These increased currents, however, enhance the firing of excitability neurons but suppress that of inhibitory neurons. We further show that the expression of Na V channel subunits, particularly that of Na V 1.6, is upregulated and that the length of the axon initial segment and of axonal Na V immunostaining is increased in both neuron types. Our study on the coordinate regulation of K Na currents and the expression of Na V channels may provide an avenue for understanding and treating epilepsies and other neurological disorders.