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Ann. Neurol., First published:20 June 2020 | https://doi.org/10.1002/ana.25827 Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

Seung-Hyun Lee, PhD,^1,#Yinhua Zhang, BSc,^2,3,#Jina Park, PhD,⁴ Bowon Kim, MSc,⁴ Yangsik Kim, MD, PhD,^5,6 Sang Hoon Lee, PhD,⁷ Gyu Hyun Kim, MSc,⁷ Yang Hoon Huh, PhD,⁸ Bokyoung Lee, MSc,² Yoonhee Kim, MSc,^2,3 Yeunkum Lee, PhD,^2,3 Jin Yong Kim, MD, PhD,^3,9 Hyojin Kang, PhD,¹⁰ Su-Yeon Choi, PhD,^5,6 Seil Jang, PhD,^5,6 Yan Li, PhD,^5,6 Shinhyun Kim, MSc,^2,3 Chunmei Jin, MSc,^2,3 Kaifang Pang, PhD,^11,12 Eunjeong Kim, PhD,¹³ Yoontae Lee, PhD,¹³ Hyun Kim, MD, PhD,^3,9 Eunjoon Kim, PhD,^5,6 Jee Hyun Choi, PhD,⁴ Jeongjin Kim, PhD,⁴ Kea Joo Lee, PhD,^7,14,* Se-Young Choi, PhD,^1,* Kihoon Han, PhD,^2,3,*

¹Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul, South Korea;
²Department of Neuroscience, College of Medicine, Korea University, Seoul, South Korea;
³Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea;
⁴Center for Neuroscience, Korea Institute of Science and Technology, Seoul, South Korea;
⁵Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon, South Korea;
⁶Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea;
⁷Neural Circuits Research Group, Korea Brain Research Institute, Daegu, South Korea;
⁸Center for Electron Microscopy Research, Korea Basic Science Institute, Chungcheongbuk-do, Korea;
⁹Department of Anatomy, College of Medicine, Korea University, Seoul, South Korea;
¹⁰Division of National Supercomputing, KISTI, Daejeon, South Korea;
¹¹Department of Pediatrics, Baylor College of Medicine, Houston, USA;
¹²Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, USA;
¹³Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea;
¹⁴Department of Brain and Cognitive Sciences, DGIST, Daegu, South Korea

^#Seung-Hyun Lee and Yinhua Zhang share first authorship.

^*Corresponding author

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 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.

논문정보

TOP52020년 후보

형식Research article
게재일2020년 06월 (BRIC 등록일 2020-06-26)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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