Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior.

Abstract

Haploinsufficiency of the AT-rich interactive domain 1B (ARID1B) gene causes autism spectrum disorder (ASD) and intellectual disability, however, the neurobiological basis for this is unknown. Here, we generated Arid1b knockout mice and examined heterozygotes to model human patients. Arid1b heterozygous mice showed a decreased number of cortical GABAergic interneurons and reduced proliferation of interneuron progenitors in the ganglionic eminence. Arid1b haploinsufficiency also led to an imbalance between excitatory and inhibitory synapses in the cerebral cortex. Furthermore, we found that Arid1b haploinsufficiency suppressed histone H3 lysine 9 acetylation (H3K9Ac) overall, and in particular reduced H3K9Ac of the Pvalb promoter, resulting in decreased transcription. Arid1b heterozygous mice exhibited abnormal cognitive and social behavior, which was rescued by treatment with a positive allosteric GABAA receptor modulator. Our results demonstrate a critical role for the Arid1b gene in interneuron development and behavior, and provide insight into the pathogenesis of ASD and intellectual disability.