Abstract
Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD. Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basis, we tested the hypothesis that changes in the endocannabinoid tone contribute to the altered phenotype induced by prenatal VPA exposure in rats, with focus on behavioral features that resemble the core and associated symptoms of ASD. In the course of development, VPA-exposed rats showed early deficits in social communication and discrimination, compromised sociability and social play behavior, stereotypies and increased anxiety, thus providing preclinical proof of the long-lasting deleterious effects induced by prenatal VPA exposure. At the neurochemical level, VPA-exposed rats displayed altered phosphorylation of CB1 cannabinoid receptors in different brain areas, associated with changes in anandamide metabolism from infancy to adulthood. Interestingly, enhancing anandamide signaling through inhibition of its degradation rescued the behavioral deficits displayed by VPA-exposed rats at infancy, adolescence and adulthood. This study therefore shows that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors and that the endocannabinoid system may represent a therapeutic target for the core and associated symptoms displayed by autistic patients.
Highlights
Autism spectrum disorders (ASD) are a group of severe developmental psychiatric disorders emerging in the early life, for which no specific treatments are currently available
When VPAand SAL-exposed animals were treated with URB597 or its vehicle, a two-way analysis of variance (ANOVA) analysis performed on the percentage of time spent sniffing the stimulus gave the following results: PND 35 (F(prenatal treat.)1,40 = 6.05, P o 0.05; F(treat.)1,40 = 9.31, P o 0.01; F(prenatal treat. × treat.)1,40 = 2.1; P = NS); PND 90 (F(prenatal treat.)1,35 = 4.13, P o 0.05; F(treat.)1,35 = 1.07, P = NS; F(prenatal treat. × treat.)1,35 = 1.1; P = NS)
By using a well-validated animal model of ASD based on prenatal valproic acid (VPA) exposure in rats,[15,16] we provide new evidence that an altered anandamide tone that manifests already at infancy and persists into adolescence and adulthood may underlie core and associated autistic-like symptoms, providing preclinical rationale to a potential role of anandamide signaling as a new therapeutic target for ASD
Summary
Autism spectrum disorders (ASD) are a group of severe developmental psychiatric disorders emerging in the early life, for which no specific treatments are currently available. ASD are characterized by altered social interaction, compromised verbal and nonverbal communication, stereotyped and repetitive behaviors,[1] often associated with comorbid features,[2,3,4] such as social and generalized anxiety.[5,6,7] Both genetic and environmental factors are involved in the etiology of ASD.[8,9] Environmental factors include a broad range of influences, such as prenatal exposure to drugs, environmental chemicals, infectious agents, or maternal stress.[10] One of the best examples of known environmental risk factors for ASD is prenatal exposure to the antiepileptic and mood stabilizer drug valproic acid (VPA). Buffer (Pierce Chemical, Rockford, IL, USA) for 15 min at room temperature and re-probed with anti-tubulin (Sigma, Catalog No T9026) antibody
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