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Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction

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Title
Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction
Author(s)
Seung-Hyun Lee ; Yinhua Zhang ; Jina Park ; owon Kim ; Yangsik Kim ; Sang Hoon Lee ; Gyu Hyun Kim ; Yang Hoon Huh ; Bokyoung Lee ; Yoonhee Kim ; Yeunkum Lee ; Jin Yong Kim ; Hyojin Kang ; Su-Yeon Choi ; Seil Jang ; Yan Li ; Shinhyun Kim ; Chunmei Jin ; Kaifang Pang ; Eunjeong Kim ; Yoontae Lee ; Hyun Kim ; Eunjoon Kim ; Jee Hyun Choi ; Jeongjin Kim ; Kea Joo Lee ; Se-Young Choi ; Kihoon Han 
Publication Date
2020-09
Journal
ANNALS OF NEUROLOGY, v.88, no.3, pp.526 - 543
Publisher
WILEY-BLACKWELL
Abstract
© 2020 American Neurological Association This article is protected by copyright. All rights reserved.OBJECTIVE: Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS: We performed behavioral analyses on Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses on Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with viral injections. RESULTS: Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA-sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Viral-mediated CYFIP2 reduction in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION: These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. This article is protected by copyright. All rights reserved
URI
https://pr.ibs.re.kr/handle/8788114/7665
DOI
10.1002/ana.25827
ISSN
0364-5134
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > 1. Journal Papers (저널논문)
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