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

Abstract

Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B) , a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created validated to characterize and define neuroanatomical, behavioural and tran­scriptional phenotypes. Neuroanatomy was assess ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones.Results - Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, during neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. As adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Limitations – The behaviour and the neuroimaging analysis were done on separate cohorts of mice, which does not allow a direct correlation between the imaging and behavioural findings. Conclusions – This study represents a full investigation of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.