Neural hyperactivity is a core pathophysiological change induced by deletion of an autism risk gene Ash1l in the mouse brain

Abstract

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Previous genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). Recent studies demonstrate that loss of Ash1l in the mouse brain is sufficient to induce ASD/ID-like behavioral and cognitive memory deficits, suggesting that disruptive ASH1L mutations are likely to be the causative driver leading to the ASD/ID pathogenesis in human patients. However, the brain pathophysiological changes underlying the Ash1l-deletion-induced ASD/ID-like behavioral and memory deficits remain unknown. Here we show loss of Ash1l in the mouse brain causes locomotor hyperactivity and higher metabolic rates . In addition, the mutant mice display lower thresholds for the convulsant reagent-induced epilepsy and increased neuronal activities in broad brain areas. Thus, our current study reveals that neural hyperactivity is a core pathophysiological change in the Ash1l-deficient mouse brain, which provides a brain-level basis for further studying the cellular and molecular mechanisms underlying the Ash1l-deletion-induced ASD/ID pathogenesis.