The Role of Fgf9 in the Antidepressant Effects of Exercise and Fluoxetine in Chronic Unpredictable Mild Stress Mice

The neurotrophic hypothesis of depression posits that stress and depression decrease neurotrophic factor expression in brain, whereas antidepressants and exercise can contribute to the blockade of stress effects and produce antidepressant effects. Fibroblast growth factor 9 (FGF9), a member of the fibroblast growth factor (FGF) family, has been reported to be dysregulated in depression. The present study aimed to determine whether and how Fgf9 mediates the antidepressant effects of fluoxetine and exercise in chronic unpredictable mild stress (CUMS) mice.Male C57BL/6 mice were exposed to CUMS for 7 weeks. From the fourth week, CUMS-exposed mice were subjected to fluoxetine treatment or swimming exercise for 4 weeks. Forced swim test, tail suspension test, and hole-board test were used to assess behaviors of mice. Real-time polymerase chain reaction was used to examine hippocampal messenger RNA levels of Fgf9, Fgf2, FgfR1, FgfR2, and FgfR3. Western blotting was used to examine the protein levels of Fgf9, protein kinase B (Akt), and phosphorylation of Akt at Ser473 in mouse hippocampus.Our results demonstrated that CUMS induced depression-like behaviors, which were reversed by fluoxetine treatment and swimming exercise. Moreover, we found that CUMS resulted in a dysregulation of Fgf9, Fgf2, and FgfR2 expression, whereas fluoxetine and swimming restored the FGF expression in CUMS-exposed mice. An analysis of the proteins suggests that the antidepressant effects of fluoxetine and exercise in CUMS-exposed mice were associated with ameliorated Fgf9/Akt signaling.Our findings have demonstrated that swimming exercise mimics the antidepressant effects of fluoxetine by regulating Fgf9 in CUMS-exposed mice, which may offer new mechanism-based therapeutic targets for depression.