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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

Kan Yang, Yuhan Shi, Xiujuan Du, 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
doi: https://doi.org/10.1101/2021.01.24.427868
Kan Yang
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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  • For correspondence: zqiu@ion.ac.cn feili@shsmu.edu.cn kanyang@ion.ac.cn jkcheng@shsmu.edu.cn
Yuhan Shi
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Xiujuan Du
2Department 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
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Yuefang Zhang
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Shifang Shan
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Yiting Yuan
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Ruoqing Wang
6Zhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
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Chenhuan Zhou
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
5University of Chinese Academy of Sciences, Beijing, 100049, China
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Yuting Liu
6Zhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
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Zilin Cai
6Zhiyuan College, School of Life Sciences and Technology, Shanghai Jiao Tong University, Shanghai, 200240, China
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Yanzhi Wang
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
5University of Chinese Academy of Sciences, Beijing, 100049, China
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Liu Fan
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Huatai Xu
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
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Juehua Yu
2Department 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
4NHC Key Laboratory of Drug Addiction Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
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Jinke Cheng
3Department of Molecular Cellular Biology, College of Basic Medical Sciences, Shanghai Jiao Tong University, Shanghai, 200025, China
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  • For correspondence: zqiu@ion.ac.cn feili@shsmu.edu.cn kanyang@ion.ac.cn jkcheng@shsmu.edu.cn
Fei Li
2Department 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
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  • For correspondence: zqiu@ion.ac.cn feili@shsmu.edu.cn kanyang@ion.ac.cn jkcheng@shsmu.edu.cn
Zilong Qiu
1Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai, 200031, China.
5University of Chinese Academy of Sciences, Beijing, 100049, China
7Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, 201210, China
8National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
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  • For correspondence: zqiu@ion.ac.cn feili@shsmu.edu.cn kanyang@ion.ac.cn jkcheng@shsmu.edu.cn
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Abstract

Autism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Leading contact: zqiu{at}ion.ac.cn (Z. Qiu)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 25, 2021.
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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
Kan Yang, Yuhan Shi, Xiujuan Du, 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
bioRxiv 2021.01.24.427868; doi: https://doi.org/10.1101/2021.01.24.427868
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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice
Kan Yang, Yuhan Shi, Xiujuan Du, 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
bioRxiv 2021.01.24.427868; doi: https://doi.org/10.1101/2021.01.24.427868

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