Functional and morphological alterations in animal models of valproic acid exposure

Valproic acid (VPA) is an antiepileptic and mood-stabilizing drug; however, it also produces side effects. This review examines how VPA exposure influences neurodevelopment, endocrine regulation, reproduction, and sex-dependent outcomes, providing an integrated interpretation of its biological consequences. VPA modifies chromatin structure, gene expression, neuronal differentiation, and synaptic development, generating functional and morphological alterations in the nervous system. Animal models of prenatal VPA exposure have been used to characterize these alterations and explore underlying mechanisms related to neurodevelopmental disorders. In rodents, VPA produces imbalances between excitatory/inhibitory (E/I) synaptic activity, neurotransmitters and morphological brain changes. Behaviorally, VPA exposed animals in utero show deficits in social interaction, sensory processing, communication, cognition, and increased stereotyped behaviors, phenotypes paralleling core features of autism spectrum disorder (ASD). Besides, VPA induces sexual dimorphism where males are the most affected. VPA also induces endocrine and reproductive abnormalities, including altered steroidogenesis, ovarian dysfunction, and impaired spermatogenesis. Importantly, postnatal environmental interventions as environmental enrichment, enhanced socialization, and early handling partially rescue neurobehavioral and neurochemical deficits, highlighting neural plasticity and experience-dependent reprogramming. The evidence reviewed supports an integrative framework where neurodevelopmental, endocrine, and behavioral alterations are understood as interacting processes across biological levels, rather than independent domains. It integrates central neurodevelopmental changes with systemic outcomes, evaluates enriched environments as non-pharmacological rescue strategies, addresses limitations of VPA model, and proposes future research directions. This review is guided by the central question of how prenatal VPA exposure produces interacting neurodevelopmental, endocrine, and behavioral alterations across biological levels, ultimately shaping long-term functional outcomes.