Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior

Haploinsufficiency of the AT-rich interactive domain 1B ( ARID1B ) gene causes autism spectrum disorder 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 particularly reduced H3K9ac of the Pvalb promoter, resulting in decreased transcription. Arid1b -heterozygous mice exhibited abnormal cognitive and social behaviors, which were rescued by treatment with a positive allosteric GABA A receptor modulator. Our results demonstrate a critical role for Arid1b in interneuron development and behavior and provide insight into the pathogenesis of autism spectrum disorder and intellectual disability. Arid1b haploinsufficiency causes autism and intellectual disability, yet the neurobiological basis of this is unknown. The authors demonstrate that Arid1b -heterozygous mice have impaired cortical interneuron development and epigenetic signatures. These mice also have cognitive and social deficits, which are reversed by treatment with a GABA A -receptor-positive allosteric modulator.