title: Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior.
abstract: Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs.
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China; Kunming Institute of Zoology/The Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Disease, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China; Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China;
authors.forename: Anping
authors.initials: A
authors.lastname: Chai
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Lifang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Zhiliu
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Hao
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Liwei
authors.initials: L
authors.lastname: Mei
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China; Peking University-International Data Group/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China;
authors.forename: Weihua
authors.initials: W
authors.lastname: Yue
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China; Kunming Institute of Zoology/The Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Disease, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China; Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China; daizhang@bjmu.edu.cn lxu@vip.163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: School of Life Sciences, Peking University, Beijing 100871, China; Peking University-International Data Group/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Rao
authors.affiliation: Institute of Mental Health, Sixth Hospital of Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorders, Ministry of Health (Peking University), Beijing 100191, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), Beijing 100191, China; Peking University-International Data Group/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Shenzhen Key Laboratory for Neuronal Structural Biology, Shenzhen Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, 518035, China daizhang@bjmu.edu.cn lxu@vip.163.com.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000523:psychology*; D056547:CA1 Region, Hippocampal / Q000503:physiopathology*; D056915:DNA Copy Number Variations; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036881:Long-Term Synaptic Depression; D051379:Mice; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D016194:Receptors, N-Methyl-D-Aspartate
keywords: AMPA receptor endocytosis; P-Rex1; autism; long-term depression; social recognition