What We Have Learned about Autism Spectrum Disorder from Valproic Acid

Abstract

Two recent epidemiological investigations in children exposed to valproic acid (VPA) treatment in utero have reported a significant risk associated with neurodevelopmental disorders and autism spectrum disorder (ASD) in particular. Parallel to this work, there is a growing body of animal research literature using VPA as an animal model of ASD. In this focused review we first summarize the epidemiological evidence linking VPA to ASD and then comment on two important neurobiological findings linking VPA to ASD clinicopathology, namely, accelerated or early brain overgrowth and hyperexcitable networks. Improving our understanding of how the drug VPA can alter early development of neurological systems will ultimately improve our understanding of ASD.

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…VPA is primarily used as a drug for seizure and epilepsy control in humans. VPA has long been known to cause developmental disabilities and physical malformations (Chomiak et al, 2013). Recently, a large-scale population-based study demonstrated that prenatal VPA exposure significantly increases the risk of ASD (Bromley et al, 2013).…”

The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?

“…In addition, high doses of the monocarboxylic HDAC inhibitors propionate or valproate, administered either systemically to the mother during pregnancy or intraventricular in adulthood were repeatedly shown to induce autistic-like symptoms in animal models (Chomiak et al, 2013;Macfabe, 2012;MacFabe et al, 2011MacFabe et al, , 2007Roullet et al, 2013;Thomas et al, 2012), suggesting extreme care has to be given to evaluation of the potential use of SCFAs in treatment of ASDs. Interestingly, however, the prenatal valproate-induced mouse model could also be treated with butyrate or even valproate when given at 4 weeks of age for 5 weeks, which was accompanied by increased histone H3 acetylation in the case of butyrate (Takuma et al, 2014).…”

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats

“…Owing to this correlation between in-utero VPA exposure and the increased risk of autism, the VPA rodent model was developed (Rodier et al, 1996;Arndt et al, 2005;Bromley et al, 2009Bromley et al, , 2013Bath and Scharfman, 2013). Pregnant dams exposed to a single dose of VPA on gestational day 12.5 produce progeny that show behavioral and neuroanatomical anomalies that are similar to those present in humans with autism (Rodier et al, 1996(Rodier et al, , 1997Schneider and Przewlocki, 2005;Rinaldi et al, 2008;Snow et al, 2008;Mychasiuk et al, 2012;Chomiak et al, 2013).…”