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 Kim; Yoontae Lee; Hyun Kim; Eunjoon Kim; Jee Hyun Choi; Jeongjin Kim; Kea Joo Lee; Se Young Choi; Kihoon Han

doi:10.1002/ana.25827

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

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Abstract

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 language	English
Pages (from-to)	526-543
Number of pages	18
Journal	Annals of Neurology
Volume	88
Issue number	3
DOIs	https://doi.org/10.1002/ana.25827
State	Published - 1 Sep 2020

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@article{6dc380c0f1644bcab0aeb62e6976d62e,

title = "Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction",

abstract = "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.",

author = "Lee, {Seung Hyun} and Yinhua Zhang and Jina Park and Bowon Kim and Yangsik Kim and Lee, {Sang Hoon} and Kim, {Gyu Hyun} and Huh, {Yang Hoon} and Bokyoung Lee and Yoonhee Kim and Yeunkum Lee and Kim, {Jin Yong} and Hyojin Kang and Choi, {Su Yeon} and Seil Jang and Yan Li and Shinhyun Kim and Chunmei Jin and Kaifang Pang and Eunjeong Kim and Yoontae Lee and Hyun Kim and Eunjoon Kim and Choi, {Jee Hyun} and Jeongjin Kim and Lee, {Kea Joo} and Choi, {Se Young} and Kihoon Han",

note = "Publisher Copyright: {\textcopyright} 2020 American Neurological Association",

year = "2020",

month = sep,

day = "1",

doi = "10.1002/ana.25827",

language = "English",

volume = "88",

pages = "526--543",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "3",

}

Lee, SH, Zhang, Y, Park, J, Kim, B, Kim, Y, Lee, SH, Kim, GH, Huh, YH, Lee, B, Kim, Y, Lee, Y, Kim, JY, Kang, H, Choi, SY, Jang, S, Li, Y, Kim, S, Jin, C, Pang, K, Kim, E, Lee, Y, Kim, H, Kim, E, Choi, JH, Kim, J, Lee, KJ, Choi, SY & Han, K 2020, 'Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction', Annals of Neurology, vol. 88, no. 3, pp. 526-543. https://doi.org/10.1002/ana.25827

TY - JOUR

T1 - Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction

AU - Lee, Seung Hyun

AU - Zhang, Yinhua

AU - Park, Jina

AU - Kim, Bowon

AU - Kim, Yangsik

AU - Lee, Sang Hoon

AU - Kim, Gyu Hyun

AU - Huh, Yang Hoon

AU - Lee, Bokyoung

AU - Kim, Yoonhee

AU - Lee, Yeunkum

AU - Kim, Jin Yong

AU - Kang, Hyojin

AU - Choi, Su Yeon

AU - Jang, Seil

AU - Li, Yan

AU - Kim, Shinhyun

AU - Jin, Chunmei

AU - Pang, Kaifang

AU - Kim, Eunjeong

AU - Lee, Yoontae

AU - Kim, Hyun

AU - Kim, Eunjoon

AU - Choi, Jee Hyun

AU - Kim, Jeongjin

AU - Lee, Kea Joo

AU - Choi, Se Young

AU - Han, Kihoon

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85088588741&partnerID=8YFLogxK

U2 - 10.1002/ana.25827

DO - 10.1002/ana.25827

M3 - Article

C2 - 32562430

AN - SCOPUS:85088588741

SN - 0364-5134

VL - 88

SP - 526

EP - 543

JO - Annals of Neurology

JF - Annals of Neurology

IS - 3

ER -

Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction

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