Sh3rf2 Haploinsufficiency Leads to Unilateral Neuronal Development Deficits and Autistic-Like Behaviors in Mice

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 devel...

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Bibliographic Details
Published in:	Cell reports (Cambridge) Vol. 25; no. 11; pp. 2963 - 2971.e6
Main Authors:	Wang, Shuo, Tan, Ningdong, Zhu, Xingliang, Yao, Minghui, Wang, Yaqing, Zhang, Xiaohui, Xu, Zhiheng
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 11-12-2018 Elsevier
Subjects:	Animal Communication Animals autism spectrum disorders Autistic Disorder - genetics Autistic Disorder - pathology Behavior, Animal brain development Cell Membrane - metabolism Cell Membrane - pathology Dendritic Spines - pathology Haploinsufficiency - genetics Hippocampus - pathology Male Mice, Inbred C57BL Mice, Knockout Neurons - pathology Oncogene Proteins - genetics Oncogene Proteins - metabolism Pyramidal Cells - metabolism Pyramidal Cells - pathology Receptors, Glutamate - metabolism Sh3rf2/POSHER Social Behavior Stereotyped Behavior Synapses - metabolism synaptic function Ubiquitin-Protein Ligases - genetics brain development Sh3rf2/POSHER autism spectrum disorders synaptic function
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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. [Display omitted] •Sh3rf2 is necessary for dendritic spine development and synaptogenesis•Sh3rf2 haploinsufficiency leads to autistic-like behaviors in mice•Disturbances in the hippocampal function of the heterozygote were selectively unilateral 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2018.11.044