In this study, we used chronic restraint stress to establish a mouse model of depression, and differentially expressed proteins in the medial prefrontal cortex of depressive model mice were detected by TMT proteomics. By functional enrichment analysis of the differentially expressed proteins, we found that CRS-induced mice have altered synaptic function and excessive autophagy. In addition, we also demonstrated that CRS may disrupt synaptic plasticity by affecting activation of the Wnt2b/尾-catenin pathway which may help explain the pathogenesis of depression and identify new antidepressant drug targets.