Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression

Chaodong Ding; Wei Zhou; Yuhan Shi; Shifang Shan; Yiting Yuan; Yuefang Zhang; Fei Li; Zilong Qiu

doi:10.1016/j.celrep.2024.114231

Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression

Cell Rep. 2024 May 10;43(5):114231. doi: 10.1016/j.celrep.2024.114231. Online ahead of print.

Authors

Chaodong Ding¹, Wei Zhou², Yuhan Shi³, Shifang Shan³, Yiting Yuan⁴, Yuefang Zhang⁴, Fei Li², Zilong Qiu⁵

Affiliations

¹ Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
² MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Developmental and Behavioral Pediatric & Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
⁴ Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Songjiang Research Institute, Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China; MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: qiuzilong@shsmu.edu.cn.

PMID: 38733588
DOI: 10.1016/j.celrep.2024.114231

Abstract

Mutations in the SRCAP gene are among the genetic alterations identified in autism spectrum disorders (ASD). However, the pathogenic mechanisms remain unclear. In this study, we demonstrate that Srcap^+/- mice manifest deficits in social novelty response, as well as increased repetitive behaviors, anxiety, and impairments in learning and memory. Notably, a reduction in parvalbumin-positive neurons is observed in the retrosplenial cortex (RSC) and dentate gyrus (DG) of these mice. Through RNA sequencing, we identify dysregulation in 27 ASD-related genes in Srcap^+/- mice. Specifically, we find that Srcap regulates expression of Satb2 via H2A.z in the promoter. Therapeutic intervention via retro-orbital injection of adeno-associated virus (AAV)-Satb2 in neonatal Srcap^+/- mice leads to amelioration of the neurodevelopmental and ASD-like abnormalities. Furthermore, the expression of Satb2 only in the RSC of adolescent mice rectifies social novelty impairments. These results underscore the pivotal role of Srcap in neurodevelopment, by regulating Satb2, providing valuable insights for the pathophysiology of ASD.

Keywords: CP: Neuroscience; SRCAP; autism spectrum disorders; parvalbumin-positive neurons; retrosplenial cortex; social behaviors.