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

Cell reports 2021 Nov 02

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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. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

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. 2021 Nov 02;37(5):109939