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

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 a...

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Published in:Cell reports (Cambridge) 2020-10, Vol.33 (4), p.108303-108303, Article 108303
Main Authors: Shore, Amy N., Colombo, Sophie, Tobin, William F., Petri, Sabrina, Cullen, Erin R., Dominguez, Soledad, Bostick, Christopher D., Beaumont, Michael A., Williams, Damian, Khodagholy, Dion, Yang, Mu, Lutz, Cathleen M., Peng, Yueqing, Gelinas, Jennifer N., Goldstein, David B., Boland, Michael J., Frankel, Wayne N., Weston, Matthew C.
Format: Article
Language:English
Subjects:
Action Potentials - genetics
ADNFLE
Animals
calcium imaging
Disease Models, Animal
electrocorticography
electrophysiology
epilepsy
Epilepsy - genetics
GABAergic Neurons - metabolism
Humans
KCNT1
KNa current
MEA
Mice
Nerve Tissue Proteins - metabolism
Potassium Channels, Sodium-Activated - metabolism
Seizures - genetics
Slack
synaptic transmission
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Summary: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. [Display omitted] •In humans, KCNT1 GOF variants cause severe epilepsy and intellectual disability•KCNT1 GOF increases subthreshold KNa currents selectively in GABAergic neurons•KCNT1 GOF impairs GABAergic neuron excitability and alters synaptic connectivity•Mice expressing a Kcnt1 GOF variant exhibit seizures and cognitive impairments Shore et al. generate a mouse model of a GOF variant in the Na+-activated K+ channel gene KCNT1 that causes a childhood epilepsy disorder. In mice, KCNT1 GOF reduces the excitability of cortical GABAergic neurons and increases homotypic synaptic connectivity, resulting in disrupted E/I balance, network hyperexcitability, and seizures.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.108303