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

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.