Consequences of prenatal exposure to valproic acid in the socially monogamous prairie voles

Abstract

Environmental risk factors contribute to autism spectrum disorders (ASD) etiology. In particular, prenatal exposure to the highly teratogenic anticonvulsant valproic acid (VPA) significantly increases ASD prevalence. Although significant discoveries on the embryopathology of VPA have been reported, its effects on the ability to form enduring social attachment—characteristic of ASD but uncommonly displayed by rats and mice—remains unknown. We aimed to examine the effects of prenatal VPA exposure in the social, monogamous prairie voles ( Microtus ochrogaster ). Compared to prenatal vehicle-exposed controls, prenatal VPA-exposed prairie voles had lower body weight throughout postnatal development, engaged in fewer social affiliative behaviors in a familial context, exhibited less social interactions with novel conspecifics, and showed enhanced anxiety-like behavior. Along these behavioral deficits, prenatal VPA exposure downregulated prefrontal cortex vasopressin receptor (V1aR) and methyl CpG-binding protein 2 (MeCP2) mRNA expression, but did not alter spine density in adults. Remarkably, adult social bonding behaviors, such as partner preference formation and selective aggression, were not disrupted by prenatal VPA exposure. Collectively, these studies suggest that, in this animal model, VPA alters only certain behavioral domains such as sex-naive anxiety and affiliative behaviors, but does not alter other domains such as social bonding with opposite sex individuals.

Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

“…Male mice exposed to VPA exhibited social impairment and reduced social interaction, manifested by lack of preference for a stranger mouse in the three-chamber test [23,24,25]. On the other hand, increased repetitive behavior and anxiety-like behaviors was reported in both males and females [23,26].…”

An anticonvulsive drug, valproic acid (valproate), has effects on the biosynthesis of fatty acids and polyketides in microorganisms

“…It is possible that when patients taking high doses of VPA, i.e., 600 mg to 900 mg, the amount of VPA in patient gastrointestinal tract may reach at the concentration of 100 µM, which may affect the fatty acid biosynthesis in gut microbiome of patients. VPA induced abnormal autism-like behaviors in mice 8 , and many studies showed the possible risk of VPA on autism spectrum disorders [9][10][11][12][13][14] . The present work demonstrated that the biosynthesis of certain fatty acids was completely inhibited by VPA, while that of some fatty acids was induced by VPA.…”

Individual differences in social attachment: A multi‐disciplinary perspective

“…A large body of rodent work indicates that perinatal interventions can alter neuroendocrine profiles and social behavior as adults 79,140 . In prairie voles, early life interventions include variation in parental care, social enrichment and external stressors, 166–169 as well as biochemical interventions like exposures to exogenous neuropeptides and valproic acid 167,170,171 . Specifically, biparental care may impact AVP receptor expression in the male prairie vole cortex.…”