Objective To establish a novel long-term depression ( LTD) model in mice, and to compare this model with the common depression mouse model. Methods Using early maternal separation and persistent chronic stress after weaning to prepare LTD mice, which were then compared with chronic unpredictable mild stress and early life stress mice to observe potential differences in their long-term depression-like behaviors. The changes in hippocampal neurons of LTD mice expressing transgenic eGFP were also observed. Results Compared with chronic unpredictable mild stress and early life stress mice, LTD mice showed a stable state of depression in animal behavior experiments. Degeneration of the hippocampal CA1 and CA3 regions of LTD mice was observed in tissue sections. Conclusions The LTD mouse model was successfully established. LTD mice provide a model suitable for the investigation of long-term simulation of depression, which can lead to long-term depression-like behavior and psychological stress.