Objective The endogenous cystatin C (CysC), encoded by the CST3 gene, is highly expressed in the brain and has protective effects in a variety of neuropathological processes. The aim of this research is to investigate whether knocking out (KO) CysC in gerbils can induce an animal model of depression and the protective effect of CysC on endothelial cells and neuronal cells under simulated pathological conditions.Methods The transcription level of CysC in different tissues of CysC knockout (CysC-KO) gerbils was detected using qPCR. The behavior of CysC-KO gerbils was evaluated through sucrose preference test (SPT), social interaction (SI), novel object recognition test (NOR), light/dark boxes, and open field trials (OFT). And under the pathological conditions simulated by H&S (hypoxic and starvation) or OGD/R (oxygen glucose deprivation/reoxygenation) or inflammatory factor (TNF-α/LPS), MTT assay was used to detect the effect of CysC or its inhibitor on HUVEC (human umbilical vein endothelial cells) and N2a (mouse neuroblastoma N2a cells) viability.Results CysC expression in CysC-KO gerbils was significantly reduced in various tissues, especially in the brain. Deficiency of CysC in gerbils induces depression-like behavior, but does not affect motion and exploration behavior. CysC significantly improved proliferation of both endothelial cell and neuronal cells under H&S, OGD and inflammatory conditions, while CysC inhibitor harbored contrary effect.Conclusion The CysC-KO gerbils exhibited depression-like behavior, which may be caused by the loss of the protective effect of CysC in vascular endothelial cells and neuronal cells. These results provide a new gerbil model for studying the neuroprotective effects of CysC and the mechanism of depression.