Reduced GABAergic Neuron Excitability, Altered Synaptic Connectivity, and Seizures in a KCNT1 Gain-of-Function Mouse Model of Childhood Epilepsy
Amy N. Shore, Sophie Colombo, William F. Tobin, Sabrina Petri, Erin R. Cullen, Soledad Domínguez, Christopher D. Bostick, Michael Beaumont, Damian J. Williams, Dion Khodagholy, Mu Yang, Cathleen Lutz, Yueqing Peng, Jennifer N. Gelinas, David B. Goldstein, Michael J. Boland, Wayne N. Frankel, Matthew C. Weston
Abstract
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 (AP) 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.