Objective To reveal the mechanism of Zuogui Jiangtang Jieyu Formula (左归降糖解郁方, ZGF) to improve synaptic loss of hippocampal neuron based on triggering receptor expressed on myeloid cells 2 (TREM2)/complement component 1q (C1q) signaling-mediated microglial cell synaptic pruning in diabetes-related depression (DD) rats. Methods The model of DD rats was established and rats were randomly divided into control group, model group, TREM2 inhibitor (IN1, 1.5 μg/kg) group, TREM2 agonist (AL002, 2 μg/kg) group, positive drug (metformin 0.18 g/kg+ fluoxetine 1.8 mg/kg) group and ZGF (10.26 g/kg) group. Primary microglia and hippocampal neurons from SD rats were cultured separately. An in vitro co-culture cell model simulating the DD environment was constructed by treating with 150 mmol/L high glucose combined with 200 μmol/L corticosterone, control group, model group, TREM2 inhibitor (IN1, 2 μmol/L) group, TREM2 agonist (AL002, 5 μmol/L) group, positive drug (10% positive drug-containing serum) group and ZGF (10% ZGF-containing serum) group were set up. Depression-like behavior was evaluated by open field, forced swimming and sucrose preference test. Synaptic loss of hippocampal neuron was observed by Golgi staining. Morphology and structure of microglia and hippocampal neuron was observed by cell imaging analysis. Nissl’s staining was used to observe synaptic loss of hippocampal neuron. The protein expressions of TREM2 and C1q in rat hippocampal microglia or in vitro microglia, and ostsynaptic density protein 95 (PSD95) in rat hippocampal neurons or in vitro hippocampal neurons were detected by immunofluorescence. The expressions of TREM2 protein in hippocampal tissue or in vitro microglia were detected by Western blotting. Results The animal experiment results showed that ZGF significantly increased the total activity distance and sugar water preference rate of rats in open field experiment (P < 0.01), reduced forced swimming immobility time (P < 0.01), up-regulated TREM2 expression in hippocampal microglia (P < 0.01), and inhibited C1q/PSD95 signal mediated excessive pruning of microglial synapses, thereby improving synaptic loss in rat hippocampal neurons (P < 0.05, 0.01). The results of cell experiments showed that the serum containing ZGF could significantly up-regulate TREM2 expression and inhibit C1q/PSD95 signal mediated synaptic pruning in microglia, thereby reversing synaptic loss in hippocampal neurons (P < 0.05, 0.01). Conclusion ZGF effectively mitigate the synaptic loss of hippocampal neuron and thereby alleviate depressive behavior in rats, the mechanism of which might be related to the regulation of excessive synaptic pruning of microglia mediated by TREM2/C1q signaling.

diabetes-related depression  /  TREM2/C1q signaling  /  synaptic pruning  /  synaptic loss  /  Zuogui Jiangtang Jieyu Formula  /  loganin  /  paeoniflorin  /  salvianolic acid B  /  calycosin-7-O-β-D-glucoside  /  catalpol