A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, few pharmacological treatments exist to alleviate these socio-behavioural impairments. Prenatal administration of valproic acid (VPA) has become an accepted animal model of ASD and has been extensively used to explore new pharmacotherapies in rodents. We conducted a systematic review of the behavioural impairments induced by the VPA model in rodents, with specific reference to 3 core socio-behavioural alterations associated with ASD: repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. We systematically reviewed studies attempting to alleviate these core behavioural alterations using pharmacological means. We include 132 studies exploring the prenatal effects of VPA in rodents. Gestational exposure to VPA in rodents has significant effects on rodent-equivalent measures of the 3 core behavioural traits characteristic of ASD in humans, inducing social impairments, repetitive behaviour, and cognitive rigidity/inflexibility after birth. This model's validity has seen it used to test potential drug treatments for ASD and is likely to continue doing so. We conclude the rodent VPA model may be suitable to examine future therapeutic interventions for ASD, providing an overview of the progress made so far.

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

“…Despite significant changes in global DNA methylation in male offspring, we found no changes in the methylation status of the promoters of the Nlgn3, Setd1b, and Taok2 genes, which could explain their increased expression in our model. It is worth noting that the observation of increased DNA methylation at PND 28 correlates with our previous RNA-seq studies in which most (45) among the top 75 differentially expressed genes affected by maternal diet were downregulated in the HFD group at the same time point, in the frontal cortex [30]. Our data indicate that an altered intrauterine developmental environment is crucial for the DNA methylation pattern in the offspring's brain (impaired in ASD individuals), but this epigenetic mechanism does not account for all the changes in gene expression, and other components of the epigenetic machinery should be investigated to fully explain the observed changes.…”

“…Moreover, mouse and rat offspring exposed to a maternal HFD are characterized by increased aggressive behavior in adulthood [ 43 , 44 ]. Furthermore, in another environmental ASD model, that is, prenatal exposure to valproic acid (VPA) [ 45 , 46 ], as well as in BTBR mice [ 7 ], decreased social episodes were noted. Altogether, our behavioral assessment indicates a strong relationship between a maternal HFD as a condition of predisposition to an autistic-like phenotype in adolescent male offspring, and our results correspond well with other preclinical autism models and epidemiological findings, showing a link between autism and obesity [ 39 ].…”

Sex-specific differences in the gut microbiota and fecal metabolites in an adolescent valproic acid-induced rat autism model

“…A single intraperitoneal injection of VPA in the second trimester of pregnant rats is well known to establish a rat autism model in offspring [44,45]. This model manifests characteristic autism symptoms and has been widely accepted to be useful for exploration of the pathogenesis of ASD [51][52][53][54]. Recently, Liu et al [43] investigated the taxonomical characterization of the GM in male and female VPA rats.…”

“…An altered F/B ratio is tightly related to ASD and obesity [24,32,46,[55][56][57], but the results in different studies are inconsistent. The incidence of obesity is significantly increased in ASD individuals [57][58][59][60][61], while the body weight of VPA rats is significantly lighter than that of Ctrl rats [49,51]. Thus, it is difficult to speculate on the internal mechanism of the altered F/B ratio in the pathogenesis of ASD.…”

On the Digital Psychopharmacology of Valproic Acid in Mice

“…However, consensus recommendations regarding the relatively improved neuropsychiatric teratogenic safety profile (or lack thereof ) for many newer anticonvulsants are conspicuously absent (Harden et al, 2009;Bromley and Baker, 2017). In support of a direct teratogenic role for valproate, offspring born to pregnant rodent dams (rats or mice) challenged briefly with valproic acid at the approximate time of neural tube closure display behavioral phenotypes deemed "autism-like, " and which are also observed in several genetically informed mouse models of autism (Crawley, 2007;Kazdoba et al, 2016;Tartaglione et al, 2019;Chaliha et al, 2020). While these studies have unraveled some mechanistically informative insights (Roullet et al, 2013;Nicolini and Fahnestock, 2018;Tartaglione et al, 2019;Chaliha et al, 2020), two main caveats limit their translational potential.…”