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Triple-phase VPA administration in Sprague-Dawley rats: A cost-effective ASD model unveiling the
Zhaoming Liu1, Caixia Wu2, Zuoxian Lin3
1Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Aims:
To overcome limitations of traditional single-dose valproic acid (VPA) models in autism spectrum disorder (ASD) research-including severe maternal toxicity and imprecise embryonic exposure-this study established a cost-effective ASD model using a three-phase sequential VPA strategy in Sprague-Dawley (SD) rats.
Materials And Methods:
Pregnant SD rats received VPA (400 → 450 → 400 mg·kg-1) on gestational days 11.5, 12.5, and 13.5. Maternal/neonatal survival, neurodevelopmental milestones, and behavioral phenotypes (open field, three-chamber sociability, repetitive grooming) were assessed. Synaptic ultrastructure (transmission electron microscopy), neuroinflammation (ELISA for IL-1β, IL-6, TNF-α, IL-10), and oxidative stress (CAT, SOD, GSH-Px, MDA) in the prefrontal cortex were analyzed.
Key Findings:
The optimized protocol eliminated maternal mortality (p < 0.01) and resorption (p < 0.0001), while enhancing neonatal survival (p < 0.01) and litter size (12-16 pups). Model rats exhibited core ASD phenotypes: social deficits (p < 0.0001), repetitive grooming (P < 0.01), and delayed neurodevelopment. Synaptic vesicle depletion, mitochondrial cristae disruption, proinflammatory cytokine upregulation (p < 0.01), and antioxidant suppression (p < 0.01) confirmed synaptic-mitochondrial-inflammatory axis dysregulation. SD rats outperformed C57BL/6 mice in phenotypic fidelity and modeling efficiency.
Significance:
This study pioneers a three-phase VPA strategy that balances high ASD phenotyping fidelity with animal welfare. The synaptic-mitochondrial-inflammatory axis is identified as a novel therapeutic target. SD rats provide a superior, cost-effective platform for ASD mechanism and intervention studies.
