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 2024-01-19T16:34:25Z 2024-01-19T16:34:25Z 2021-09-05 2020-09 0364-5134 https://pubs.kist.re.kr/handle/201004/118174 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 forCYFIP2-associated brain disorders remain largely unknown. Here, we characterizedCyfip2heterozygous (Cyfip2(+/-)) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of theCyfip2(+/-)mice and specified a neuronal function mediating its efficacy. Methods We performed behavioral analyses ofCyfip2(+/-)mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses ofCyfip2(+/-)prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. Results AdultCyfip2(+/-)mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adultCyfip2(+/-)PFC that was restricted to layer 5 (L5) neurons. Consistently, adultCyfip2(+/-)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 ofCyfip2(+/-)L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adultCyfip2(+/-)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 adultCyfip2(+/-)mice, which can be implicated inCYFIP2-associated brain disorders. ANN NEUROL 2020 English WILEY DENDRITIC SPINES OSCILLATIONS PROTEINS CHANNELS INSIGHTS BEHAVIOR DELETION DENSITY NETWORK AUTISM Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction Article 10.1002/ana.25827 1 ANNALS OF NEUROLOGY, v.88, no.3, pp.526 - 543 ANNALS OF NEUROLOGY 88 3 526 543 scie scopus 000552494700001 2-s2.0-85088588741 Clinical Neurology Neurosciences Neurosciences & Neurology Article DENDRITIC SPINES OSCILLATIONS PROTEINS CHANNELS INSIGHTS BEHAVIOR DELETION DENSITY NETWORK AUTISM