Nature neuroscience, 2018-04, Vol.21 (4), p.564
2018
Details
- Autor(en) / Beteiligte
- Titel
- Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition
- Ist Teil von
- Nature neuroscience, 2018-04, Vol.21 (4), p.564
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1546-1726DOI: 10.1038/s41593-018-0110-8Titel-ID: cdi_pubmed_primary_29531362
- Format
- –
- Schlagworte
- Animals, Autistic Disorder - complications, Autistic Disorder - genetics, Depsipeptides - therapeutic use, Disease Models, Animal, Exploratory Behavior - drug effects, Gene Expression Regulation - drug effects, Gene Expression Regulation - genetics, Grooming - drug effects, Grooming - physiology, Histone Deacetylase Inhibitors - therapeutic use, Histone Deacetylases - metabolism, Locomotion - drug effects, Locomotion - genetics, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Nerve Tissue Proteins - deficiency, Nerve Tissue Proteins - genetics, Nerve Tissue Proteins - metabolism, Prefrontal Cortex - pathology, Psychomotor Performance - drug effects, Social Behavior Disorders - enzymology, Social Behavior Disorders - etiology, Social Behavior Disorders - therapy, Synaptic Potentials - drug effects, Synaptic Potentials - genetics