Objective:To explore the effects and mechanisms of E2 on cognitive disorder induced by chronic mild stress (CMS) of depressive female ovariectomized (OVX) mice. Methods:We used CMS as the animal model for stress-induced depression,and detected plasma corticosterone of normal and depressive mice. Then,we examined whether 7 days treatment using E2 could ameliorate the effects of CMS on plasma E2 in female OVX mice. Morris water maze was performed to test spatial learning and memory ability of mice after last treatment. At the same time,we analyzed the mRNA and protein expression of nitric oxide synthase (nNOS) in hippocampus as well as positive nNOS neurons of dentate gyrus. Primary cultured hippocampal neurons from female embryo were adopted,the mRNA and protein expressions of nNOS were detected in neurons exposed to corticosterone (CORT) or CORT combined with E2 for 24 h. In addition,we detected the level of extracellular signal-regulated kinase (ERK) phosphorylation in neurons exposed to E2 for 24 h. Results:Plasma CORT of female and male mice was significantly increased after CMS. Ectogenic supplement of E2 reversed the decrease of plasma E2 and spatial learning and memory deficit,as well as the decrease of hippocampal nNOS mRNA and protein expression induced by CMS in female OVX mice. In vitro,E2 reversed nNOS mRNA and protein expression induced by corticosterone in primary cultured cortical hippocampal neurons from female embryo. In addition,E2 significantly up-regulated ERK phosphorylation in the hippocampal neurons from female embryo. Conclusion:E2 could reverse the spatial learning and memory deficits and abnormal hippocampal nNOS expression induced by chronic stress in female OVX mice. The hippocampal neuronal ERK phosphorylation is involved in the effects of E2.