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

被引：14

作者：

Oh, Hyoseon ^{[1
,2
]}

Lee, Suho ^{[2
]}

Oh, Yusang ^{[1
,3
]}

Kim, Seongbin ^{[1
]}

Kim, Young Seo ^{[4
]}

Yang, Yeji ^{[1
,5
]}

Choi, Woochul ^{[3
]}

Yoo, Ye-Eun ^{[2
]}

Cho, Heejin ^{[2
]}

Lee, Seungjoon ^{[2
]}

Yang, Esther ^{[6
,7
]}

Koh, Wuhyun ^{[8
]}

Won, Woojin ^{[8
]}

Kim, Ryunhee ^{[2
]}

Lee, C. Justin ^{[8
]}

Kim, Hyun ^{[6
,7
]}

Kang, Hyojin ^{[9
]}

Kim, Jin Young ^{[5
]}

Ku, Taeyun ^{[4
]}

Paik, Se-Bum ^{[3
]}

Kim, Eunjoon ^{[1
,2
]}

机构：

[1] Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, Daejeon 34141, South Korea

[2] Inst Basic Sci IBS, Ctr Synapt Brain Dysfunct, Daejeon 34141, South Korea

[3] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Daejeon 34141, South Korea

[4] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon 34141, South Korea

[5] Korea Basic Sci Inst, Res Ctr Bioconvergence Anal, 162 Yeongudanjiro, Cheongju 28119, Chungbuk, South Korea

[6] Korea Univ, Dept Anat, Coll Med, Biomed Sci, Seoul 02841, South Korea

[7] Korea Univ, Brain Korea 21 Grad Program, Coll Med, Biomed Sci, Seoul 02841, South Korea

[8] Inst for Basic Sci Korea, Ctr Cognit & Social, Daejeon 34126, South Korea

[9] Korea Inst Sci & Technol Informat, Div Natl Supercomp, Daejeon 34141, South Korea

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

AXON INITIAL SEGMENT; EPILEPSY-ASSOCIATED KCNQ2; NEURONAL EXCITABILITY; MECHANISMS; EXPRESSION; ANKYRIN(B); DISEASES; SODIUM; L1;

D O I：

10.1038/s41467-023-39203-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：20

共 4 条

[1] 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
Eunjoon Kim
Nature Communications, 14
[2] New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels
Michael A. Rogawski
Carl W. Bazil
Current Neurology and Neuroscience Reports, 2008, 8 : 345 - 352
[3] New molecular targets for Antiepileptic drugs:: α2δ, SV2A, and Kv7/KCNQ/M potassium channels
Rogawski, Michael A.
Bazil, Carl W.
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, 2008, 8 (04) : 345 - 352
[4] MEDI 150-Discovery and biological evaluation of novel 2-acetamido-indoles as potent and selective openers of Kv7/KCNQ potassium channels
Christos, Thomas E.
McNaughton-Smith, Grant
Atkinson, Robert N.
Secrest, Matthew E.
Gerlach, Aaron C.
Conary, Scott D.
Antonio, Brett M.
Stoehr, Sally J.
Roeloffs, Rosemarie
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 234

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