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.
Berand Neuropharmacology, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin 4, Ireland.
Andrew G
AG
Foley
Berand Neuropharmacology, NovaUCD, Belfield Innovation Park, University College Dublin, Dublin 4, Ireland.
Andrew W
AW
Cassidy
School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: ciaran.regan@ucd.ie.
Ciaran M
CM
Regan
D000107:Acetylation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000201:enzymology; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000523:psychology; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D018811:Maternal Exposure; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017208:Rats, Wistar; D012919:Social Behavior; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C434604:pentyl-4-yn-valproic acid; D000077337:Vorinostat; D014635:Valproic Acid
H3K9ac; SAHA; Social cognition; VPA