Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior

Eui Man Jung, Jeffrey Jay Moffat, Jinxu Liu, Shashank M. Dravid, Channabasavaiah Basavaraju Gurumurthy, Woo Yang Kim

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1694-1707
Number of pages14
JournalNature Neuroscience
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Haploinsufficiency
Interneurons
Intellectual Disability
Social Behavior
GABA-A Receptors
Acetylation
Heterozygote
Knockout Mice
Cerebral Cortex
Histones
Synapses
Lysine
Genes
Autism Spectrum Disorder
Therapeutics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. / Jung, Eui Man; Moffat, Jeffrey Jay; Liu, Jinxu; Dravid, Shashank M.; Gurumurthy, Channabasavaiah Basavaraju; Kim, Woo Yang.

In: Nature Neuroscience, Vol. 20, No. 12, 01.12.2017, p. 1694-1707.

Research output: Contribution to journalArticle

Jung, Eui Man ; Moffat, Jeffrey Jay ; Liu, Jinxu ; Dravid, Shashank M. ; Gurumurthy, Channabasavaiah Basavaraju ; Kim, Woo Yang. / Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. In: Nature Neuroscience. 2017 ; Vol. 20, No. 12. pp. 1694-1707.
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