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. 1. Introduction The core clinicopathology of autism spectrum disorder (ASD) is currently thought to be characterized by accelerated or early brain tissue overgrowth in regions involved in emotional, social, and communication functions [1–6]. Although much of the earlier evidence regarding accelerated or early brain overgrowth was based on head circumference measurements which may not be as robust as previously thought [7] (but see [8]), more recent longitudinal brain imaging studies have provided further evidence of this abnormal pattern of brain growth in ASD [3, 6]. In fact, abnormal pathological overgrowth in ASD may even persist into adulthood in certain brain regions [9]. Exposure to exogenous chemicals during pregnancy can interfere with cortical development and the maturation of offspring. One such exogenous chemical is the short chain fatty acid valproic acid (VPA). VPA is a drug used in humans primarily for epilepsy and seizure control, although it has been used in many nonepileptic conditions as well [10]. Based on several case studies and small-scale population-based studies in humans [11–16], in addition to mounting experimental evidence in animals [17–32], VPA has known teratogenicity and has long been suspected as a risk factor for ASD. This year, however, both a prospective study and a large-scale population-based study were published providing the most substantial evidence to date linking prenatal VPA exposure to an increased risk of ASD [33, 34]. Thus, in this paper we will review epidemiological evidence linking VPA to ASD and will discuss two promising leads in the study of ASD in light of human clinical findings and the valproic acid animal model of ASD. 2. Valproic Acid and ASD: Epidemiological Evidence Previous links between the antiepileptic drug VPA and ASD have been found and explored
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