The identification of a novel electrophysiological endophenotype in the Valproic Acid rat model of autism unveils new disease pathways for the development of specific pharmacological treatments

Prenatal exposure to the antiepileptic drug valproic acid (VPA) induces autism spectrum disorder (ASD) in humans and autistic-like behaviors in rodents, which makes it a good model to study the neural underpinnings of ASD (Bromley et al. 2008; Gail Williams and Hersh 1997; Roullet, Lai, and Foster 2013). According to the DSM-5 diagnostic criteria, persistent deficits in social communication and social interaction are key features of ASD. The pervasive social deficits found in autistic patients have been initially explained in terms of cognitive impairments and inability to infer others’ mental states. More recently, they have been related to blunted social reward processing, i.e., inability to enjoy and prolong reciprocal social interactions, which has been hypothesized to be the consequence of the abnormal activity of the brain reward circuit in social contexts (C. Chevallier et al. 2012; Pellissier et al. 2018). In agreement, functional MRI studies in both children and adults with ASD, showing significant impairment in social skills measured by the ADI-R subscale, demonstrate the reduction in mesolimbic (ML) reward pathway functional connectivity (Supekar et al. 2018). Along this line, the social dysfunctions displayed by VPA-exposed rats may be caused by either their inability to properly understand and respond to social signals by the social partner or by a failure of their reward system to assign a positive value to the social experience. Thus, we hypothesize that the social impairment displayed by VPA-exposed rats could be caused by a dysfunction in the mesolimbic reward pathway.