Glu-mGluR2/3-ERK Signaling Regulates Apoptosis of Hippocampal Neurons in Diabetic-Depression Model Rats

OBJECTIVES: Diabetes mellitus is frequently accompanied by depression (diabetes−depression, DD), and DD patients are at higher risk of diabetes-related disability and mortality than diabetes patients without depression. Hippocampal degeneration is a major pathological feature of DD. Here, we investigated the contribution of the Glu−mGluR2/3−ERK signaling pathway to apoptosis of hippocampal neurons in DD model rats. METHODS: The DD model was established by high-fat diet (HFD) feeding and streptozotocin (STZ) injection followed by chronic unpredictable mild stress (CUMS). Other groups were subjected to HFD + STZ only (diabetes alone) or CUMS only (depression alone). Deficits in hippocampus-dependent memory were assessed in the Morris water maze (MWM), motor activity in the open field test (OFT), and depression-like behavior in the forced swim test (FST). Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) was used to estimate the rate of hippocampal neuron apoptosis. Hippocampal glutamate (Glu) content was measured by high performance liquid chromatography. Hippocampal expression levels of mGluR2/3, ERK, and the apoptosis effector caspase-3 were estimated by immunohistochemistry and Western blotting. RESULTS: DD model rats demonstrated more severe depression-like behavior in the FST, greater spatial learning and memory deficits in the MWM, and reduced horizontal and vertical activity in the OFT compared to control, depression alone, and diabetes alone groups. All of these abnormalities were reversed by treatment with the mGluR2/3 antagonist LY341495. The DD group also exhibited greater numbers of TUNEL-positive hippocampal neurons than all other groups, and this increased apoptosis rate was reversed by LY341495. In addition, hippocampal expression levels of caspase-3 and mGluR2/3 were significantly higher, ERK expression was lower, and Glu was elevated in the DD group. The mGluR2//3 antagonist significantly altered all these features of DD. CONCLUSIONS: Comorbid diabetes and depression are associated with enhanced hippocampal neuronal apoptosis and concomitantly greater hippocampal dysfunction. These pathogenic effects are regulated by the Glu−mGluR2/3−ERK signaling pathway.