Abstract: OBJECTIVE To explore the effects of Zuogui Jiangtang Jieyu Fang on diabetes mellitus plasticity of synaptic function in hippocampal neurons of diabetes mellitus model rats with depression according to the expression of NR receptor subtype and its downstream molecular CaMKII, SynGAP. METHODS The diabetes mellitus with depression rat model was established, and the rats were randomly divided into 4 groups: model group, positive drug group (metformin 0.18 g·kg^-1+fluoxetine hydrochloride 1.8 mg·kg^-1), Zuogui Jiangtang Jieyu Fang high and low dose group (32.82, 8.20 g·kg^-1), normal rats were in blank control group. Morris test was used to detect the behavior of the rats. The expression of NR2A, NR2B, SynGAP and CaMKII was detected by Western-blotting. RESULTS Compared with blank control group, the escape latencies were longer, the space exploration times were significantly shortened(P<0.05), and the expression of NR2A, NR2B, SynGAP and CaMKII were significantly increased(P<0.01) in model group. Compared with the model group, the escape latencies were significantly longer(P<0.05), the space exploration times were significantly shortened(P<0.05) and the expression of NR2A, NR2B, SynGAP and CaMKII were significantly decreased(P<0.05 or 0.01) in Zuogui Jiangtang Jieyu Fang group. CONCLUSION Zuogui Jiangtang Jieyu Fang can significantly enhance the learning and memory ability, improving cognitive dysfunction, and relieve the depressive symptoms in diabetes mellitus with depression model rats. The effect may be related with the protection of synaptic function in hippocampal neurons through regulating the expression of NR receptor subtype and its downstream molecules SynGAP and CaMKII.