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

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.

Neural symptoms in a gene knockout mouse model of Sjögren‐Larsson syndrome are associated with a decrease in 2‐hydroxygalactosylceramide

“…Twelve trials were conducted in total: 6 with a wide beam (2.5 cm diameter) followed by 6 with a narrow beam (0.8 cm diameter). Moving speed (cm/s), number of movement initiations, and number of paw slips were recorded and analyzed with ImageBT software (39).…”

Neuroanatomy and Behaviour in Mice with a Haploinsufficiency of AT-Rich Interactive Domain 1B (ARID1B) Throughout Development

“…Of the 82 Arid1b +/+ used in this study, only one was excluded due to hydrocephalus, a rate of 1.2%. Occurrence of hydrocephalus has been previously reported in Arid1b +/mice models at rates of 5.5% to 6.6% 17,19 . These rates were mouse models that had severe hydrocephaly and thus were excluded from the study, but it should be noted that the ventricular system as a whole was enlarged in Arid1b +/mice throughout development (q=0.005), particularly the lateral ventricles (q=2.0x10 -12 ).…”

“…Celen et al reported that the corpus callosum was smaller in adult Arid1b +/mice compared to WT 17 , confirming what is seen in a proportion of the human patients. Conversely, while the corpus callosum was not directly assessed in Shibutani et al, they made a general statement that there were no histological abnormalities observed in the Arid1b +/compared to WT 19 , but they did not directly assess the corpus callosum volume. In our ex vivo whole brain analysis of adult mice we did not find a difference in the size of the corpus callosum, and in fact, we found an increase in the size of the corpus callosum across development in our in vivo longitudinal cohort.…”

“…Moreover, having a rigorous reproducible model system allows for the testing of medicinal or genetic interventions and developing therapeutics. Three groups have recently published papers examining mouse models of Arid1b haploinsufficiency [17][18][19] . In those studies, the authors report several behavioural abnormalities relevant to ASD phenotypes, including cognitive and social behaviour deficits.…”

“…However, in none of these previous investigations of Arid1b mutant mice was a full brain neuroanatomical assessment performed. One study focused on only two areas relevant to CSS 17 , and the other two groups did not specifically look for neuroanatomical alterations 18,19 , but rather focussed on smaller microscopic differences in cortical structures. Moreover, these studies examined limited windows of time, focusing only on adulthood for their neuroanatomical and behavioural assessments.…”