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

2020; Cell Press; Volume: 33; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2020.108303

2639-1856

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,

Neural dynamics and brain function

Gain-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 (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.