Autism-like behavior Increases with age and is predated by molecular changes in Arid1b haploinsufficient mice.

Abstract

Genetic studies have revealed that ARID1B haploinsufficiency leads to autism spectrum disorder (ASD). Given the dynamic development of the brain and behavior, understanding the critical developmental window that influences the onset and severity of ASD-like behavior linked to ARID1B haploinsufficiency is important. Using an Arid1b haploinsufficient mouse model of ASD, we investigated age-dependent ASD-like behaviors at postnatal days 30, 60, and 120. We found that while wild type mice exhibited maturation of social and anxiety-like behaviors over the developmental window, Arid1b haploinsufficient mice showed no progression in the maturation of these behaviors. We also examined oxytocin expression in various brain regions across different developmental stages. Oxytocin mRNA levels in different brain regions were downregulated in Arid1b haploinsufficient mice throughout development and remained reduced with age. Finally, we explored corticosterone expression in Arid1b haploinsufficient mice to determine whether the allostatic regulation between oxytocin and corticosterone is altered in the context of social threat. Both wild type and Arid1b haploinsufficient mice displayed elevated corticosterone levels after social threat. However, Arid1b haploinsufficient mice showed significantly higher corticosterone and lower oxytocin levels than controls, suggesting disrupted allostatic regulation between oxytocin and corticosterone in Arid1b haploinsufficient mice. Our results show that the Arid1b haploinsufficient condition impairs the maturation of social and anxiety-like behaviors associated with ASD, with molecular alterations preceding behavioral deficits in this condition.