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 Dominguez; Christopher D Bostick; Michael A Beaumont; Damian Williams; Dion Khodagholy; Mu Yang; Cathleen M Lutz; Yueqing Peng; Jennifer N Gelinas; David B Goldstein; Michael J Boland; Wayne N Frankel; Matthew C Weston

doi:10.1016/j.celrep.2020.108303

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

Cell Rep. 2020 Oct 27;33(4):108303. doi: 10.1016/j.celrep.2020.108303.

Authors

Amy N Shore¹, Sophie Colombo², William F Tobin¹, Sabrina Petri², Erin R Cullen¹, Soledad Dominguez², Christopher D Bostick², Michael A Beaumont³, Damian Williams², Dion Khodagholy⁴, Mu Yang², Cathleen M Lutz⁵, Yueqing Peng⁶, Jennifer N Gelinas⁷, David B Goldstein⁸, Michael J Boland⁸, Wayne N Frankel⁷, Matthew C Weston⁹

Affiliations

¹ Department of Neurological Sciences, University of Vermont, Burlington, VT 05405, USA.
² Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
³ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Axion BioSystems, Atlanta, GA 30309, USA.
⁴ Department of Electrical Engineering, Columbia University, New York, NY 10032, USA.
⁵ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
⁶ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
⁷ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA.
⁸ Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
⁹ Department of Neurological Sciences, University of Vermont, Burlington, VT 05405, USA. Electronic address: mcweston@uvm.edu.

Abstract

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⁺ (K_Na) 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 K_Na currents in cortical excitatory and inhibitory neurons, there is an increase in the K_Na 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.

Keywords: ADNFLE; K(Na) current; KCNT1; MEA; Slack; calcium imaging; electrocorticography; electrophysiology; epilepsy; synaptic transmission.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / genetics*
Animals
Disease Models, Animal
Epilepsy / genetics*
GABAergic Neurons / metabolism*
Humans
Mice
Nerve Tissue Proteins / metabolism*
Potassium Channels, Sodium-Activated / metabolism*
Seizures / genetics*

Substances

KCNT1 protein, human
Nerve Tissue Proteins
Potassium Channels, Sodium-Activated

Abstract

Publication types

MeSH terms

Substances

Grants and funding