Arid1b Haploinsufficiency Causes Abnormal Brain Gene Expression and Autism-Related Behaviors in Mice.

Mihiro Shibutani,Tsuyoshi Miyakawa,Mika Kimura,Hirotaka Shoji,Sumiyo Morita,Izuho Hatada,Naomi Terawaki,Takuro Horii

doi:10.3390/ijms18091872

Mihiro Shibutani, Tsuyoshi Miyakawa + Show 6 more

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https://doi.org/10.3390/ijms18091872

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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that include poor social communication, restricted interests, and repetitive behaviors. Several ASD mouse models exhibit impaired social interaction, anxiety-like behavior, and elevated perseveration. Large-scale whole exome sequencing studies identified many genes putatively associated with ASD. Like chromodomain helicase DNA binding protein 8 (CHD8), the most frequently mutated gene in individuals with ASD, the candidate gene AT-rich interaction domain 1B (ARID1B) encodes a chromatin remodeling factor. Arid1b heterozygous knockout (hKO) mice exhibited ASD-like traits related to social behavior, anxiety, and perseveration, in addition to associated features reported in some cases of ASD, such as reduced weight, impaired motor coordination, and hydrocephalus. Hydrocephalus was present in 5 of 91 hKO mice, while it was not observed in wild-type littermates (0 of 188). Genome-wide gene expression patterns in Arid1b hKO mice were similar to those in ASD patients and Chd8-haploinsufficient mice, an ASD model, and to developmental changes in gene expression in fast-spiking cells in the mouse brain. Our results suggest that Arid1b haploinsufficiency causes ASD-like phenotypes in mice.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) by three features: impairment of social communication, restricted interests, and repetitive behaviors
We evaluated social behavior in the social interaction and three-chambers tests, but observed no significant differences between Arid1b heterozygous knockout (hKO) and WT mice
These results suggest that the impairment of social behavior in Arid1b hKO mice is mild

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) by three features: impairment of social communication, restricted interests, and repetitive behaviors. The results of twin studies suggest that genetic factors play important roles in ASD pathogenesis [8,9]. The co-occurrence of ASD in monozygotic twins is higher than that of dizygotic twins, it is not complete, suggesting that environmental factors contribute [9]. On the basis of these reports, models of autism have been generated using animals genetically modified to mimic the features of ASD patients [10,11,12,13,14,15]. Typical animal models exhibit poor social communication, anxiety, and perseveration [11]

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