Class i histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

摘要

In utero exposure of rodents to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of ASD. We employed the social approach avoidance paradigm as a measure of social reciprocity, detection of biological motion that is crucial to social interactions, and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to VPA. We found no significant change in the expression of neural cell adhesion molecule polysialylation state (NCAM PSA), a measure of construct validity, but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning. Finally, in all cases, we found chronic HDAC inhibition, with either pan-specific or HDAC1-3 isoform-specific inhibitors, to significantly ameliorate deficits in both social cognition and its associated neuroplastic response. We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive deficits of ASD and a potential screen for the development of novel therapeutics for this condition.