Sh3rf2 Haploinsufficiency Leads to Unilateral Neuronal Development Deficits and Autistic-Like Behaviors in Mice
Shuo Wang,
Ningdong Tan,
Xingliang Zhu,
Minghui Yao,
Yaqing Wang,
Xiaohui Zhang,
Zhiheng Xu
Affiliations
Shuo Wang
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
Ningdong Tan
State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
Xingliang Zhu
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China
Minghui Yao
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Yaqing Wang
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Xiaohui Zhang
State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China; Corresponding author
Zhiheng Xu
State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Parkinson’s Disease Center, Beijing Institute for Brain Disorders, Beijing 100101, China; Corresponding author
Summary: Autism spectrum disorders (ASDs) include a variety of developmental brain disorders with clinical findings implicating the dysfunction of the left hemisphere. Here, we generate mice lacking one copy of Sh3rf2, which was detected in ASD patients, to determine whether Sh3rf2 is involved in brain development and whether mutation of SH3RF2 is causative for ASD and the mechanisms linking it to ASD traits. We find that mice with Sh3rf2 haploinsufficiency display significant deficits in social interaction and communication, as well as stereotyped or repetitive behaviors and hyperactivity and seizures. Disturbances in hippocampal dendritic spine development, aberrant composition of glutamatergic receptor subunits, and abnormal excitatory synaptic transmission were detected in heterozygous mutants. Remarkably, these defects are selectively unilateral. Our results support a notion that Sh3rf2 haploinsufficiency is a highly penetrant risk factor for ASD, with disease pathogenesis most likely resulting from deficits in synaptic function in the left hemisphere of the brain. : Wang et al. find that Sh3rf2 is important for neuron development and that Sh3rf2 haploinsufficiency in mice results in typical ASD-like behaviors, as well as selective unilateral disturbances in hippocampal dendritic spine development, composition of glutamatergic receptor subunits, and excitatory synaptic transmission. Keywords: autism spectrum disorders, Sh3rf2/POSHER, brain development, synaptic function
