Pentyl-4-yn-VPA, a histone deacetylase inhibitor, ameliorates deficits in social behavior and cognition in a rodent model of autism spectrum disorders

Eur J Pharmacol. 2014 Mar 15;727:80-6. doi: 10.1016/j.ejphar.2014.01.050. Epub 2014 Jan 31.

Abstract

In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes.

Keywords: H3K9ac; SAHA; Social cognition; VPA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Behavior, Animal / drug effects*
  • Cerebellar Cortex / drug effects*
  • Cerebellar Cortex / enzymology
  • Child Development Disorders, Pervasive / chemically induced
  • Child Development Disorders, Pervasive / drug therapy*
  • Child Development Disorders, Pervasive / enzymology
  • Child Development Disorders, Pervasive / psychology
  • Cognition / drug effects*
  • Disease Models, Animal
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / metabolism
  • Hydroxamic Acids / pharmacology
  • Male
  • Maternal Exposure
  • Maze Learning / drug effects
  • Motor Activity / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Rats, Wistar
  • Social Behavior*
  • Valproic Acid / analogs & derivatives*
  • Valproic Acid / pharmacology
  • Vorinostat

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • pentyl-4-yn-valproic acid
  • Vorinostat
  • Valproic Acid