AIM: To investigate the role of fluoxetine in the hippocampal synaptic plasticity in chronic unpre-dictable mild stress (CUMS) depression rats and its effect on mTOR and autophagy signaling pathways.METHODS:Male Sprague-Dawley rats (n =60) were randomly divided into normal control group, CUMS group and fluoxetine group. The CUMS rat model was established through CUMS combined with solitary raising, and fluoxetine (20 mg? kg -1? d -1 ) was administered via intragastric gavage.The changes of body weight, the ratio of sugar intake and the results of the behav-ioral test were recorded to identify the modeling.Moreover, the expression of synaptic plasticity-related proteins glial fibril-lary acidic protein (GFAP) and synaptophysin (SYP), apoptosis-related proteins Bcl-2 and caspase-3, mTOR signaling proteins mTOR and 4EBP1, and autophagy-related proteins beclin 1 and LC3 were examined by RT-PCR and Western blot. RESULTS: Compared with control group, the body weight, sucrose intake, and total distance and intermediate residence time in the open field test were significantly decreased in CUMS group.The results of RT-PCR and Western blotting showed that the mRNA and protein levels of SYP and GFAP in CUMS group were significantly down-regulated compared with con-trol group.The expression of Bcl-2 in CUMS group was downregulated, while the protein level of cleaved caspase-3 in-creased.Decreased phosphorylation levels of mTOR and its downstream target molecule 4EBP1 were observed in CUMS group.Besides, the autophagy-related proteins beclin 1 and LC3 were significantly upregulated at mRNA and protein lev-els.All these results(upregulation or downregulation) were attenuated by the treatment with fluoxetine, and the difference was statistically significant.CONCLUSION: Fluoxetine might improve hippocampal synaptic plasticity and alleviate symp-toms of depression by supressing apoptosis/autophagy signaling pathways and upregulating mTOR signaling pathway.