Effects of β-Glucans on Pro-Inflammatory Markers and Behavioral Phenotype in a Valproic Acid (VPA)-Induced Autism Model in Zebrafish

Autism Spectrum Disorder (ASD) is a multifactorial neurodevelopmental condition in which neuroinflammation, oxidative stress, and synaptic dysfunction act as converging mechanisms. Prenatal exposure to valproic acid (VPA), an antiepileptic drug and histone deacetylase inhibitor, is a recognized environmental risk factor associated with ASD-like phenotypes. Zebrafish, with conserved neuroimmune pathways, rapid development, and quantifiable social behavior, represents a robust model for investigating ASD pathophysiology and testing therapeutic candidates. This study aimed to assess if a previously selected concentration of VPA is capable of inducing persistent alterations from early development through adulthood, and to assess the potential of β-glucans, natural polysaccharides with antioxidant and immunomodulatory properties, to mitigate VPA-induced alterations. A multimodal approach included morphological evaluation, mitochondrial respiration, quantitative PCR of inflammatory markers, and behavioral assays targeting locomotion, anxiety-like responses, and social preference. Low-dose VPA (25 μM) induced developmental and behavioral difficulties, accompanied by a transient reduction in mitochondrial respiratory capacity. β-glucan supplementation attenuated selected VPA-induced alterations, including inflammatory gene-expression changes in larvae and behavioral alterations in adulthood. Overall, these findings provide preclinical evidence that β-glucans can modulate selected VPA-induced inflammatory, molecular and behavioral alterations and support further investigation of their potential effects in neurodevelopmental models.