Ginger supplementation alleviates autistic behaviors by modulating AKT/GSK3β signaling in mice exposed to prenatal valproic acid

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and comorbid symptoms including anxiety and cognitive problems. The main pathological mechanisms underlying ASD are synaptic abnormalities and neuroinflammation. Ginger, commonly used as a spice, has been reported to enhance neurogenesis and attenuate inflammation in neurological disease; however, its effects on ASD remain unknown. This study aimed to investigate the therapeutic effects and molecular mechanisms of ginger extract (GE) in ASD. Prenatally valproic acid (VPA)-exposed mice were orally administered GE for 4 weeks from 6 weeks of age. Behavioral tests were performed to assess social interaction, anxiety, and cognitive functions. Network pharmacology and molecular docking analyses were used to predict targets and mechanisms of GE in ASD, which were verified using western blotting. Histological changes, including neurogenesis, neuroinflammation, and synaptic formation, were analyzed using immunostaining, western blotting, and qRT-PCR. GE ameliorated VPA-induced social deficits, anxiety-like behavior, and memory impairments. Network pharmacology identified AKT as a core molecular target of GE, and its active compounds exhibited high binding affinity for AKT. Consistent with these predictions, GE increased AKT and GSK3β phosphorylation in the hippocampus of mice, thereby restoring neuronal development, as evidenced by the increased Ki67- and DCX-positive cells. GE also mitigated gliosis and reduced STAT3 phosphorylation and TNF-α upregulation, thereby suppressing neuroinflammation and synaptic loss. GE alleviates ASD-like behaviors by promoting neuronal and synaptic development while suppressing neuroinflammation through AKT/GSK3β signaling, highlighting its potential as a natural supplement for ASD prevention.