Article

Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior

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Abstract

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 GABAA 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.

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Acknowledgements

We thank S. Bonasera for helping with the behavioral analysis. Research reported in this publication was supported by an award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS091220 and an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under award number P20GM103471 to W.-Y.K.

Author information

Affiliations

  1. Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA

    • Eui-Man Jung
    • , Jeffrey Jay Moffat
    • , Channabasavaiah Basavaraju Gurumurthy
    •  & Woo-Yang Kim
  2. Department of Pharmacology, Creighton University, Omaha, Nebraska, USA

    • Jinxu Liu
    •  & Shashank Manohar Dravid

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Contributions

E.-M.J. and W.-Y.K. designed, performed and analyzed the experiments and wrote the paper. J.J.M., C.G. and J.L. performed the experiments. S.M.D. designed and analyzed the experiments. W.-Y.K. conceived and supervised the study.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Woo-Yang Kim.

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