Exercise-induced FNDC5/irisin promote stress resilence in mice by targeting astrocytic GLT1 in the amygdala

Physical exercise (PE) benefits both physical fitness and cognitive function. As a major source of myokines, skeletal muscle links PE to brain health. Irisin, cleaved from FNDC5, is a PE-induced myokine that crosses the blood-brain barrier and is also expressed in neurons, suggesting complex roles in the central nervous system. In this study, mice were subjected to 4 weeks of treadmill exercise (15  m/min, 30  min/day, 3  days/week). PE reduced anxiety‑like behaviors in open field and elevated plus maze tests and upregulated FNDC5/irisin in the amygdala. Amygdalar FNDC5/irisin knockdown abolished the anxiolytic effects of PE, while local overexpression recapitulated them. Mechanistically, FNDC5/irisin suppressed amygdalar neuronal excitability and excitatory synaptic transmission through astrocytic glutamate transporter‑1 (GLT1). Based on the GLT1‑FNDC5 binding interface, we identified the small molecule AG‑205/36953163 (AG205, SPECS library ID: 36953163). Intraperitoneal administration of AG‑205 (1  mg·kg^-1·d^-1, 3  days) exerted significant anxiolytic effects. Our findings reveal that FNDC5/irisin in the amygdala mediates the anxiolytic effects of PE via direct neural regulation, offering a potential target for anxiety‑related disorders.