Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women.Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition,while the effect of FSH on menopausal depression has remained undefined.In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr-/-).We found that Fshr-/-mice displayed aggravated depression-like behaviors,accompanied by severe oxidative stress in the whole brain,resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition.Importantly,administration of ROS scavenger N-acetyl cysteine (NAC,150 mg· kg-1· d-1,i.p.for 12 weeks) attenuated the depression-like behaviors of Fshr-/-mice.Consistent with these in vivo experiment results,we found that pretreatment with FSH (50,100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD,and decreased the ROS production in N2a mouse neuroblastoma cells.These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression,and likely to maintain the redox-optimized ROS balance in neurons.