정희정 (University of Illinois at Urbana-Champaign) | 한빛사논문 > 한빛사

한빛사논문

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University of Illinois at Urbana-Champaign

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Proc. Natl. Acad. Sci. USA, December 21, 2021, 118 (51) : e2021265118 | https://doi.org/10.1073/pnas.2021265118 Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of Kv7.2

Eung Chang Kim^a, Jiaren Zhang^a, Andy Y. Tang^a, Eric C. Bolton^a, Justin S. Rhodes^b,c,d, Catherine A. Christian-Hinman^a,b,d, and Hee Jung Chung^a,b,d,1

^aDepartment of Molecular and Integrative Physiology, University of Illinois at Urbana- Champaign, Urbana, IL 61801; ^bBeckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; ^cDepartment of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and ^dNeuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801

¹To whom correspondence may be addressed.

Abstract

Epileptic encephalopathy (EE) is characterized by seizures that respond poorly to antiseizure drugs, psychomotor delay, and cognitive and behavioral impairments. One of the frequently mutated genes in EE is KCNQ2, which encodes the Kv7.2 subunit of voltage-gated Kv7 potassium channels. Kv7 channels composed of Kv7.2 and Kv7.3 are enriched at the axonal surface, where they potently suppress neuronal excitability. Previously, we reported that the de novo dominant EE mutation M546V in human Kv7.2 blocks calmodulin binding to Kv7.2 and axonal surface expression of Kv7 channels via their intracellular retention. However, whether these pathogenic mechanisms underlie epileptic seizures and behavioral comorbidities remains unknown. Here, we report conditional transgenic cKcnq2+/M547V mice, in which expression of mouse Kv7.2-M547V (equivalent to human Kv7.2-M546V) is induced in forebrain excitatory pyramidal neurons and astrocytes. These mice display early mortality, spontaneous seizures, enhanced seizure susceptibility, memory impairment, and repetitive behaviors. Furthermore, hippocampal pathology shows widespread neurodegeneration and reactive astrocytes. This study demonstrates that the impairment in axonal surface expression of Kv7 channels is associated with epileptic seizures, cognitive and behavioral deficits, and neuronal loss in KCNQ2-related EE.

KCNQ2, seizures, epilepsy

논문정보

형식Research article
게재일2021년 12월 (BRIC 등록일 2021-12-27)
연구진국외 연구진
분야 생명과학 > 세포생물학

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