Long-term GABA supplementation mitigates anxiety by modulating complement and neuroinflammatory pathways.

Anxiety disorders are among the most prevalent mental health conditions, often linked with neuroinflammation and imbalances in neurotransmitter systems. This study examined the anxiolytic effects of oral GABA in chronic restraint stress (CRS) mice. Mice were divided into control, CRS, and two GABA-treated groups (10 mg/kg, 20 mg/kg). After 14 days of administration, anxiety-like behaviors were assessed using elevated-plus maze and open-field tests. GABA levels in the prefrontal cortex were quantified via ELISA, while anti-inflammatory cytokines were measured using an antibody array. Proteomic analysis of the hippocampus identified differentially expressed proteins, validated through Parallel Reaction Monitoring and immunoblotting. Results showed that GABA significantly alleviated anxiety-like behaviors, increased GABA levels in the prefrontal cortex, and elevated anti-inflammatory factors IL-10 and TGF-β1. Proteomic analysis and validation revealed GABA reversed complement dysregulation (C3, C4b, Cfh, Cfi). These findings suggest GABA alleviates anxiety by modulating immune homeostasis and complement activation, highlighting its therapeutic potential.