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Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction

Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction
Lee, Seung-HyunZhang, YinhuaPark, JinaKim, BowonKim, YangsikLee, Sang HoonKim, Gyu HyunHuh, Yang HoonLee, BokyoungKim, YoonheeLee, YeunkumKim, Jin YongKang, HyojinChoi, Su-YeonJang, SeilLi, YanKim, ShinhyunJin, ChunmeiPang, KaifangKim, EunjeongLee, YoontaeKim, HyunKim, EunjoonChoi, Jee HyunKim, JeongjinLee, Kea JooChoi, Se-YoungHan, Kihoon
DGIST Authors
Lee, Seung-Hyun; Zhang, Yinhua; Park, Jina; Kim, Bowon; Kim, Yangsik; Lee, Sang Hoon; Kim, Gyu Hyun; Huh, Yang Hoon; Lee, Bokyoung; Kim, Yoonhee; Lee, Yeunkum; Kim, Jin Yong; Kang, Hyojin; Choi, Su-Yeon; Jang, Seil; Li, Yan; Kim, Shinhyun; Jin, Chunmei; Pang, Kaifang; Kim, Eunjeong; Lee, Yoontae; Kim, Hyun; Kim, Eunjoon; Choi, Jee Hyun; Kim, Jeongjin; Lee, Kea Joo; Choi, Se-Young; Han, Kihoon
Issue Date
Annals of Neurology, 88(3), 526-543
Article Type
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 the 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 of Cyfip2+/− mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/− prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus 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. Virus-mediated reduction of CYFIP2 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 the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/− mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526–543. © 2020 American Neurological Association
John Wiley & Sons Inc.
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