ARID1B Haploinsufficiency Reveals Early Divergent Neuroanatomical Phenotypes through Development and Sex

Background: Haploinsufficiency of ARID1B, the chromatin remodelling AT-Rich Interactive Gene 1B, has been implicated in autism spectrum disorder (ASD), intellectual disability and Coffin-Siris syndrome (O’Roak et al., 2012; Fitzgerald et al. 2015; Celen et al., 2017). Although ARID1B haploinsufficiency is implicated in multiple neuropsychiatric disorders, little is known about its effect on neuroanatomical development.

Objectives: This study explores the structural neuroimaging phenotypes associated with the ARID1B mutation using in vivo magnetic resonance imaging (MRI) in mice. Our aim is to elucidate any developmental and sex differences in neuroanatomical phenotypes associated with haploinsufficiency of ARID1B.

Methods: A novel Arid1b mouse model was generated in-house at the Toronto Centre for Phenogenomics. The sample consists of 11 males and 11 females, 5 of which were mutants and 6 of which were wildtype controls of each sex. Male and female Arid1b mice were scanned longitudinally over 5 early postnatal day (p) time-points: p4, p6, p8, p10 and p17. A 7.0 Tesla MRI scanner with cryocoils was used to acquire images of the mouse brains with a resolution of 75 um isotropic. Scan data was analyzed using image registration and deformation based morphometry approaches described in Qiu et al (2018). From this, the volumes of 182 distinct regions were calculated (Dorr et al 2008, Ullmann et al 2013, Steadman et al 2014). We used linear mixed effects models to determine the effect of genotype, sex and their interaction on the volumes of each region of interest over time.

Results: We found both age and sex to have a significant interaction with genotype. A significant interaction with age was discovered, showing that mutants demonstrate different growth rates, mainly decreased growth rates in the cerebellum. Upon further investigation, a significant interaction between sex and genotype demonstrated a divergent neurodevelopmental pattern in males and females. Male mice showed a stable developmental pattern of a smaller cerebellum and larger cortex over development. Female mice showed the opposite pattern initially (larger cerebellum and smaller cortex) and then demonstrated a reversal of this pattern around p12 to match male developmental patterns.

Conclusions: We plan to replicate this finding and extend the timepoints past p17 to gain a better understanding of this sex-dependent neurodevelopmental trajectory. This work demonstrates, for the first time, that structural neuroanatomical phenotypes are different for male and female Arid1b mice early in development but this divergence dissipates before p17. Given the sex differences in the prevalence of ASD and Coffin-Siris syndrome, these findings suggest that ARID1B’s interaction with neurodevelopmental patterns may be one underlying cause of this disparity.