NEUROPROTECTIVE EFFECTS OF ZINC SUPPLEMENTATION ON BEHAVIOR, SYNAPTIC INTEGRITY, AND NEUROINFLAMMATION IN PREFRONTAL CORTEX AND HIPPOCAMPUS IN A PRENATAL VALPROIC ACID-INDUCED MODEL OF AUTISM

Autism spectrum disorder is an early-onset neurodevelopmental condition characterized by social communication deficits and repetitive behaviors, with maternal zinc deficiency proposed as a potential environmental risk factor. Therefore, we aimed to investigate the effects of zinc supplementation on behavioral outcomes, synaptic protein expression, and neuroinflammatory markers in rat offspring prenatally exposed to valproic acid (VPA), a well-established model of ASD. Pregnant rats were assigned to Control, VPA, Zinc, or VPA+Zinc groups. VPA (500 mg/kg, intraperitoneally) was administered on gestational day 12.5 to induce ASD-like phenotypes, followed by zinc treatment (2 mg/kg, subcutaneously). Offspring were evaluated using ultrasonic vocalization recordings and the three-chambered social approach test to assess communication and social behavior. Synaptic scaffold and vesicle-associated proteins (SHANK3, NLGN3, synaptophysin) and proinflammatory cytokines (IL-1β, IL-6, IL-17, TNF-α) were quantified by RT-qPCR, and microglial activation was examined by immunofluorescence imaging. VPA exposure produced ASD-like behavioral deficits such as impaired social interaction and reduced communication. VPA administration reduced SHANK3 mRNA expression and elevated proinflammatory cytokine mRNA levels in the prefrontal cortex and hippocampus, accompanied by enhanced microglial activation, indicating pronounced synaptic and neuroimmune dysregulation. Zinc supplementation significantly ameliorated behavioral impairments, normalized ultrasonic vocalizations, restored synaptic protein mRNA expression, and decreased neuroinflammatory markers and microglial reactivity. Sex and region-specific differences were identified in both pathology and treatment response. Overall, the findings demonstrate that zinc exerts neuroprotective and anti-inflammatory effects in this ASD model and support its potential as an early nutritional intervention targeting synaptic integrity and neuroinflammation associated with prenatal environmental risk factors.