Kv7/KCNQ potassium channels in cortical hyperexcitability and juvenile seizure-related death in Ank2-mutant mice

Hyoseon Oh, Suho Lee, Yusang Oh, Seongbin Kim, Young Seo Kim, Yeji Yang, Woochul Choi, Ye-Eun Yoo, Heejin Cho, Seungjoon Lee, Esther Yang, Wuhyun Koh, Woojin Won, Ryunhee Kim, C. Justin Lee, Hyun Kim, Hyojin Kang, Jin Young Kim, Taeyun Ku, Se-Bum Paik and Eunjoon Kim ()
Additional contact information
Hyoseon Oh: Korea Advanced Institute for Science and Technology (KAIST)
Suho Lee: Institute for Basic Science (IBS)
Yusang Oh: Korea Advanced Institute for Science and Technology (KAIST)
Seongbin Kim: Korea Advanced Institute for Science and Technology (KAIST)
Young Seo Kim: Graduate School of Medical Science and Engineering
Yeji Yang: Korea Advanced Institute for Science and Technology (KAIST)
Woochul Choi: Department of Bio and Brain Engineering
Ye-Eun Yoo: Institute for Basic Science (IBS)
Heejin Cho: Institute for Basic Science (IBS)
Seungjoon Lee: Institute for Basic Science (IBS)
Esther Yang: Korea University
Wuhyun Koh: IBS
Woojin Won: IBS
Ryunhee Kim: Institute for Basic Science (IBS)
C. Justin Lee: IBS
Hyun Kim: Korea University
Hyojin Kang: Korea Institute of Science and Technology Information
Jin Young Kim: Korea Basic Science Institute
Taeyun Ku: Graduate School of Medical Science and Engineering
Se-Bum Paik: Department of Bio and Brain Engineering
Eunjoon Kim: Korea Advanced Institute for Science and Technology (KAIST)

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.

Date: 2023
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DOI: 10.1038/s41467-023-39203-z

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