Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction

Seung Hyun Lee, Yinhua Zhang, Jina Park, Bowon 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 KimYoontae Lee, Hyun Kim, Eunjoon Kim, Jee Hyun Choi, Jeongjin Kim, Kea Joo Lee, Se Young Choi, Kihoon Han

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)526-543
Number of pages18
JournalAnnals of Neurology
Issue number3
Publication statusPublished - 2020 Sept 1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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