SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
Kan Yang,
Yuhan Shi,
Xiujuan Du,
Jincheng Wang,
Yuefang Zhang,
Shifang Shan,
Yiting Yuan,
Ruoqing Wang,
Chenhuan Zhou,
Yuting Liu,
Zilin Cai,
Yanzhi Wang,
Liu Fan,
Huatai Xu,
Juehua Yu,
Jinke Cheng,
Fei Li,
Zilong Qiu
Affiliations
Kan Yang
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; Corresponding author
Yuhan Shi
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
Xiujuan Du
Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200049, China
Jincheng Wang
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Yuefang Zhang
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
Shifang Shan
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
Yiting Yuan
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
Ruoqing Wang
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Zhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
Chenhuan Zhou
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Yuting Liu
Zhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
Zilin Cai
Zhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
Yanzhi Wang
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Liu Fan
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
Huatai Xu
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China
Juehua Yu
Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200049, China; NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
Jinke Cheng
Department of Molecular Cellular Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai, 200025, China; Corresponding author
Fei Li
Department of Developmental and Behavioural Pediatric & Child Primary Care, Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200049, China; Corresponding author
Zilong Qiu
Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China; Corresponding author
Summary: Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, causing defects of social interaction and repetitive behaviors. Here, we identify a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene in people with ASD without neurodevelopmental delay. We find that Senp1+/− mice exhibit core autistic-like symptoms such as social deficits and repetitive behaviors but normal learning and memory ability. Moreover, we find that inhibitory and excitatory synaptic functions are severely affected in the retrosplenial agranular (RSA) cortex of Senp1+/− mice. Lack of Senp1 leads to increased SUMOylation and degradation of fragile X mental retardation protein (FMRP), also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescues the defects of synaptic function and autistic-like symptoms of Senp1+/− mice. Together, these results demonstrate that disruption of the SENP1-FMRP regulatory axis in the RSA causes autistic symptoms, providing a candidate region for ASD pathophysiology.
