Journal Article

Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition

Qin, Luye, Matas, Emmanuel, Wei, Jing, Zi-Jun, Wang, Ma, Kaijie, Yan, Zhen, Hu, Zihua

2018

Overview

Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations.

• Publisher: Nature Publishing Group
• Subject: Acetylation / Actin / Animal models / Autism / Cell adhesion / Chromatin / Filaments / Gene expression / Genes / Glutamic acid receptors (ionotropic) / Haploinsufficiency / HDAC2 protein / Histone deacetylase / Localization / Mice / Mutation / N-Methyl-D-aspartic acid receptors / Prefrontal cortex / Rodents / Transcription / β-Catenin