SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
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 neur...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721014121 |
| _version_ | 1818980446155833344 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kan Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T17:15:33Z |
| format | Article |
| id | doaj.art-6b7fd11d03ff423a94c2cbfb7a590876 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T17:15:33Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6b7fd11d03ff423a94c2cbfb7a5908762022-12-21T19:32:01ZengElsevierCell Reports2211-12472021-11-01375109939SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in miceKan Yang0Yuhan Shi1Xiujuan Du2Jincheng Wang3Yuefang Zhang4Shifang Shan5Yiting Yuan6Ruoqing Wang7Chenhuan Zhou8Yuting Liu9Zilin Cai10Yanzhi Wang11Liu Fan12Huatai Xu13Juehua Yu14Jinke Cheng15Fei Li16Zilong Qiu17Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, China; Corresponding authorCenter for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, ChinaDepartment 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, ChinaCenter 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, ChinaCenter for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, ChinaCenter for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, ChinaCenter for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, ChinaCenter 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, ChinaCenter 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, ChinaZhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, ChinaZhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, ChinaCenter 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, ChinaCenter for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, ChinaCenter for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031, ChinaDepartment 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, ChinaDepartment of Molecular Cellular Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai, 200025, China; Corresponding authorDepartment 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 authorCenter 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721014121 |
| spellingShingle | 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 SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice Cell Reports |
| title | SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice |
| title_full | SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice |
| title_fullStr | SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice |
| title_full_unstemmed | SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice |
| title_short | SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice |
| title_sort | senp1 in the retrosplenial agranular cortex regulates core autistic like symptoms in mice |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721014121 |
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