Abstract
Autism spectrum disorders (ASDs) comprise a genetically heterogeneous group of conditions characterized by a multifaceted range of impairments and multifactorial etiology. Epidemiological studies have identified valproic acid (VPA), an anticonvulsant used to treat epilepsy, as an environmental factor for ASDs. Based on these observations, studies using embryonic exposure to VPA have been conducted in many vertebrate species to model ASD. The zebrafish is emerging as a popular model in biomedical research to study the molecular pathways involved in nervous system disorders. VPA exposure in zebrafish larvae has been shown to produce a plethora of effects on social, motor and anxiety behavior, and several genetic pathways altered by VPA have been described. However, the doses and regimen of administration reported in the literature are very heterogenous, creating contradictory results and posing serious limits to the interpretation of VPA action on neurodevelopment. To shed light on the toxic effect of VPA, we tested micromolar concentrations of VPA, using exposure for 24 and 48 h in two different zebrafish strains. Our results show that micromolar doses of VPA mildly affect embryo survival but are sufficient to induce molecular alterations in neurodevelopmental genes previously shown to be influenced by VPA, with substantial differences between strains.
Highlights
Autism spectrum disorders (ASDs) comprise a multifaceted, genetically heterogeneous group of neurodevelopmental conditions characterized by a range of behavioral impairments, including deficits in social interaction, repetitive behavior and increased sensitivity to sensory stimuli
Embryos were incubated in valproic acid (VPA) (Sigma-Aldrich, P4543; Merck Life Science Srl, Milan, Italy) solutions for 24 or 48 h, and the medium was replaced by E3 medium
To shed light on the toxic effect of VPA, we exposed zebrafish larvae of two different zebrafish inbred strains to 1 μM VPA for 24 and 48 h and tested embryo survival rates and changes in the expression of neurodevelopmental genes
Summary
Autism spectrum disorders (ASDs) comprise a multifaceted, genetically heterogeneous group of neurodevelopmental conditions characterized by a range of behavioral impairments, including deficits in social interaction, repetitive behavior and increased sensitivity to sensory stimuli. Prospective and retrospective clinical studies have identified valproic acid (VPA) as an environmental factor for ASDs. VPA is an anticonvulsant used to treat epilepsy, used as a mood stabilizer to treat bipolar disorder, whose embryonic exposure has been associated with several instances of an increased risk for ASDs [1,2,3]. VPA has been shown to produce alterations in early social-orienting responses and social interaction [7,8,14]
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