PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton,modulating emotional behavior  

作　　者：Laidong Yu Fangfang Zeng Mengshu Fan Kexuan Zhang Jingjing Duan Yalu Tan Panlin Liao Jin Wen Chenyu Wang Meilin Wang Jialong Yuan Xinxin Pang Yan Huang Yangzhou Zhang Jia-Da Li Zhuohua Zhang Zhonghua Hu 

机构地区：[1]Hunan Key Laboratory of Molecular Precision Medicine,Department of Critical Care Medicine,Xiangya Hospital,Central South University,Changsha,Hunan 410008,China [2]Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics,School of Life Sciences,Central South University,Changsha,Hunan 410008,China [3]National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,Hunan 410008,China [4]Hunan Provincial Clinical Research Center for Critical Care Medicine,Xiangya Hospital,Central South University,Changsha,Hunan 410008,China [5]Hunan Key Laboratory of Animal Models for Human Diseases,School of Life Sciences,Central South University,Changsha,Hunan 410008,China [6]MOE Key Lab of Rare Pediatric Diseases,School of Life Sciences,Central South University,Changsha,Hunan 410008,China [7]Department of Neurosciences,University of South China Medical School,Hengyang,Hunan 421001,China

出　　处：《Zoological Research》2024年第3期535-550,共16页动物学研究（英文）

基　　金：supported by the National Natural Science Foundation of China(82171506 and 31872778);Discipline Innovative Engineering Plan(111 Program)of China(B13036);Key Laboratory Grant from Hunan Province(2016TP1006);Department of Science and Technology of Hunan Province(2021DK2001,Innovative Team Program 2019RS1010);Innovation-Driven Team Project from Central South University(2020CX016);Hunan Hundred Talents Program for Young Outstanding Scientists。

摘　　要：Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function.Synaptic abnormalities,such as defects in the density and morphology of postsynaptic dendritic spines,underlie the pathology of various neuropsychiatric disorders.Protocadherin 17(PCDH17)is associated with major mood disorders,including bipolar disorder and depression.However,the molecular mechanisms by which PCDH17 regulates spine number,morphology,and behavior remain elusive.In this study,we found that PCDH17 functions at postsynaptic sites,restricting the number and size of dendritic spines in excitatory neurons.Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety-and depression-like behaviors in mice.Mechanistically,PCDH17 interacts with actin-relevant proteins and regulates actin filament(F-actin)organization.Specifically,PCDH17 binds to ROCK2,increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3(Ser3).Inhibition of ROCK2 activity with belumosudil(KD025)ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression,suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development.Hence,these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior,providing pathological insights into the neurobiological basis of mood disorders.

关 键 词：Synapse development Dendritic spine Mood disorder Actin cytoskeleton Animal behavior 

分 类 号：R338[医药卫生—人体生理学]