Study of the effect of antioxidant molecules on neuroinflammatory markers and on the cognitive-behavioral phenotype in a valproic acid (VPA)-induced autism model in zebrafish

The Autism Spectrum Disorder (ASD) is a common developmental disorder characterized by persistent deficits in social communication and social interaction across multiple contexts, and by restricted, repetitive patterns of behavior, interests, or activities. Symptoms must be present in the early developmental period and must cause clinically significant impairment in social, occupational, or other important areas of functioning. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), it is included in Neurodevelopmental Disorders (NDDs), along with Attention Deficit/Hyperactivity Disorder (ADHD), intellectual disabilities, communication disorders, specific learning disorders and motor disorders, and with whom frequently coexists. Despite its high worldwide incidence, the etiology remains broadly undetermined. However, previous studies shed light on the contribution of both genetic and environmental factors to the pathogenesis of the disorder. Indeed, numerous genes, defined “ASD-risk genes”, most of which are involved in the immunologic response within the Central Nervous System (CNS), seem to have a role in the predisposition to develop ASD and to determine a pro-inflammatory/pro-oxidative environment, which have been frequently detected in autistic post-mortem human brains. Among the environmental factors, great attention has been paid to the early administration of Valproic Acid (VPA), an anti-seizure drug. VPA exposure of pregnant women has been linked to an increase in the risk of ASD, prompting the development of various VPA-induced animal models, including zebrafish. The present project utilizes the well-known VPA-induced zebrafish model of ASD to better determine the minimal effective dose of VPA required to induce a stable autism-like phenotype persisting into adulthood, and to investigate the possibility of attenuating the phenotype through a drug repositioning IV assay. Molecular and behavioral analyses were conducted to assess pro-neuroinflammatory state, oxidative stress, and social behavior, both in larvae and adult fish. In addition, we used β-glucans— natural compounds with anti-inflammatory and antioxidant properties, already tested in other disease models— to evaluate their ability to attenuate short- and long-term phenotypic manifestations of ASD in our zebrafish model.