The Role of Fgf9 in the Antidepressant Effects of Exercise and Fluoxetine in CUMS Mice.

Objective The neurotrophic hypothesis of depression posits that stress and depression decrease neurotrophic factor expression in brain, while antidepressants and exercise can contribute to the blockade of stress effects and produces 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 antidepressant effects of fluoxetine and exercise in chronic unpredictable mild stress (CUMS) mice. Methods Male C57BL/6 mice were exposed to CUMS for 7 weeks. From the 4th week, CUMS-exposed mice were subjected to fluoxetine treatment or swimming exercise for 4 weeks. Forced swim test (FST), tail suspension test (TST) and hole-board test (HBT) were used to assess behaviors of mice. Real-time PCR was used to examine hippocampal mRNA levels of Fgf9, Fgf2, FgfR1, FgfR2 and FgfR3. Western Blotting was used to examine the protein levels of Fgf9, Akt and phosphorylation of Akt at Ser473 in mouse hippocampus. Results 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 FGFs expression in CUMS-exposed mice. An analysis of the proteins suggests that the antidepressant effects of fluoxetine and exercise in CUMS-exposed mice was associated with ameliorated Fgf9/Akt signaling. Conclusions 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.