Abstract
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. Rats prenatally exposed to VPA show profound deficits in the social domain. The altered social behavior displayed by VPA-exposed rats may be due to either a deficit in social reward processing or to a more general inability to properly understand and respond to social signals. To address this issue, we performed behavioral, electrophysiological and neurochemical experiments and tested the involvement of the brain reward system in the social dysfunctions displayed by rats prenatally exposed to VPA (500 mg/kg). We found that, compared to control animals, VPA-exposed rats showed reduced play responsiveness together with impaired sociability in the three-chamber test and altered social discrimination abilities. In addition, VPA-exposed rats showed altered expression of dopamine receptors together with inherent hyperexcitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). However, when tested for socially-induced conditioned place preference, locomotor response to amphetamine and sucrose preference, control and VPA-exposed rats performed similarly, indicating normal responses to social, drug and food rewards. On the basis of the results obtained, we hypothesize that social dysfunctions displayed by VPA-exposed rats are more likely caused by alterations in cognitive aspects of the social interaction, such as the interpretation and reciprocation of social stimuli and/or the ability to adjust the social behavior of the individual to the changing circumstances in the social and physical environment, rather than to inability to enjoy the pleasurable aspects of the social interaction. The observed neurochemical and electrophysiological alterations in the NAc may contribute to the inability of VPA-exposed rats to process and respond to social cues, or, alternatively, represent a compensatory mechanism towards VPA-induced neurodevelopmental insults.
Highlights
The precise causes of autism spectrum disorder (ASD) are still the subject of significant debate, a number of factors have been identified that, interacting in complex ways, affect early brain development contributing to the risk of ASD
Since activation of dopaminergic terminals in the nucleus accumbens (NAc) of rats during bouts of interaction with novel conspecifics has been reported (Robinson et al, 2002; Gunaydin et al, 2014) and given the important role of NAc dopamine in rewarding forms of social interaction such as social play (Manduca et al, 2016), we addressed the role of the NAc in the social impairment displayed by valproic acid (VPA)-exposed rats by performing electrophysiological experiments in this brain area
While no differences were found between SAL- and VPA-exposed animals in the number of pinning (t = 0.81, p = n.s., df = 16; data not shown) and pouncing (t = −0.86, p = n.s., df = 16; data not shown), VPA-exposed rats displayed a higher frequency of partial rotation (t = −2.81, p = 0.013, df = 16; Figure 1B) compared to SAL-exposed animals
Summary
The precise causes of autism spectrum disorder (ASD) are still the subject of significant debate, a number of factors (rare gene mutations, gene variations and adverse environmental events) have been identified that, interacting in complex ways, affect early brain development contributing to the risk of ASD. When given during gestation, VPA increases the risk for various congenital malformations (Kozma, 2001; Kini et al, 2006), and induces core autistic symptoms in the offspring, i.e., impaired communication, reduced sociability and stereotyped behaviors (Williams and Hersh, 1997; Williams et al, 2001). Based on this clinical evidence, prenatal exposure to VPA in rodents has been validated as a drug-induced preclinical model of ASD (Roullet et al, 2013; Nicolini and Fahnestock, 2018; Tartaglione et al, 2019). The social deficits displayed by VPA-exposed rats are long lasting, since they persist at adulthood (Schneider and Przewłocki, 2005; Schneider et al, 2006, 2008; Markram et al, 2008; Kim et al, 2011, 2014; Servadio et al, 2016, 2018; Hirsch et al, 2018; Melancia et al, 2018; Fontes-Dutra et al, 2019) and are evocative of the social disturbances displayed by autistic patients over the course of development
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