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.

中文翻译：

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Arid1b单倍体不足会破坏皮质神经元的发育和小鼠的行为。

富含AT的互动域1B（ARID1B）基因的单倍剂量不足会导致自闭症谱系障碍和智力障碍；但是，其神经生物学基础尚不清楚。在这里，我们生成了Arid1b基因敲除小鼠，并检查了杂合子以模拟人类患者。Arid1b杂合小鼠显示神经节隆起中皮质GABA能性中枢神经元数量减少，中枢神经元祖细胞增殖减少。Arid1b单倍体不足也导致大脑皮层的兴奋性突触和抑制性突触之间的失衡。此外，我们发现Arid1b单倍体不足总体上抑制了组蛋白H3赖氨酸9乙酰化（H3K9ac），特别是降低了Pvalb启动子的H3K9ac，从而导致转录降低。Arid1b杂合子小鼠表现出异常的认知和社交行为，_一个受体调节剂。我们的结果证明了Arid1b在中间神经元发育和行为中的关键作用，并为自闭症谱系障碍和智力障碍的发病机理提供了见识。