Prenatal valproic acid exposure in rodent models of autism: a systematic review of neurobehavioral physiological alterations

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Introduction Rodent models based on prenatal valproic acid (VPA) exposure are widely used to investigate autism spectrum disorder (ASD)-related neurobehavioral and biological alterations. Over the past two years, the rapid expansion of VPA-based research incorporating advanced molecular, neuroimaging, electrophysiological, and microbiota analyses has generated a substantial but fragmented body of evidence. Methods This systematic review aimed to synthesize findings from rodent studies published between January 2024 and November 2025 that employed prenatal VPA exposure, with particular emphasis on behavioral, neurobiological, inflammatory, microbiota–gut–brain axis, gene-expression, and histopathological outcomes. A structured search was conducted in PubMed, Scopus, Web of Science Core Collection, Embase, and PsycINFO, supplemented by manual screening in Google Scholar. Controlled vocabulary and free-text terms related to ASD, VPA, and rodent models were combined. Original in vivo studies administering VPA during gestation and reporting behavioral and/or biological outcomes were included. Because of substantial heterogeneity in VPA dose, administration route, gestational timing, species, strain, sex, and outcome domains, findings were synthesized narratively. Risk of bias was assessed using the SYRCLE risk-of-bias tool, and reporting completeness was evaluated using the ARRIVE 2.0 guidelines. Results Sixty-six eligible prenatal VPA studies were included. Most administered a single intraperitoneal dose of 500 or 600 mg/kg around embryonic day 12–12.5. Across studies, prenatal VPA exposure was consistently associated with ASD-like phenotypes, including reduced sociability, impaired social novelty preference, repetitive behaviors, anxiety-like traits, and cognitive deficits. Frequently reported biological alterations included oxidative stress, neuroinflammation involving NF-κB and NLRP3 signaling, neurotransmitter dysregulation, impaired synaptic plasticity, microbiota-related changes, and region-specific brain abnormalities. Discussion Recent prenatal VPA studies therefore extend beyond classical behavioral characterization by integrating neuroimmune, oxidative, microbiota-related, transcriptomic, electrophysiological, and histopathological findings. However, substantial methodological heterogeneity and incomplete reporting of randomization, blinding, animal-flow, and litter-level procedures limit cross-study comparability, reproducibility, and translational interpretation.

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