Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy

Shore AN, Colombo S, Tobin WF, Petri S, Cullen ER, Dominguez S, Bostick CD, Beaumont MA, Williams D, Khodagholy D, Yang M, Lutz CM, Peng Y, Gelinas JN, Goldstein DB, Boland MJ, Frankel WN, Weston MC.

Cell Reports, 2020


In this paper the authors present that KCNT1 GOF variants are known to cause severe epilepsy.  This gain-of-function mutation cases an increase in subthreshold K currents selectively in GABAergic neurons impairing the neurons excitability and alters its synaptic connectivity. This results in network hyperexcitability and hypersynchronicity. 

Axion's multielectrode array (MEA) system recorded spontaneous spiking activity across the 16 electrodes in the well of both WT and Kcnt1 neuron populations. The two cell populations were shown to mature at a similar rate, measured by the increase in number of active electrodes per well.   The Kcnt1 neurons displayed the hyperexcitability phenotype which is characterized by increased mean firing rate and increased bursting frequency.  Furthermore, an increase in number of network bursts was recorded in the Kcnt1 neurons suggesting an increase in synchrony.