Microglia stimulation produces antidepressant-like effects in a mouse depression model induced by adolescent chronic unpredictable stress.

Depression triggered by harmful stress in adolescents is a common phenomenon that can lead to serious social problems. Its treatment is still frustrating in the clinic. We reported the phenomenon that a 12-day chronic unpredictable stress (CUS), starting on postnatal day 28, led to a significant decrease in the number of microglia in the dentate gyrus of the hippocampus in adult mice. Reversing this decline with a single injection of low-dose lipopolysaccharide (LPS), a classical immunostimulant, could rapidly reverse the depression-like behavior induced by 12 days of CUS stimulation during adolescence. In the dose-dependent experiment, a single injection of LPS at doses of 75 and 100 μg/kg, but not at doses of 25 and 50 μg/kg, produced an antidepressant effect in mice exposed to 12-day CUS during adolescence. The time-dependent experiment showed that the antidepressant effect of the single injection of LPS (100 μg/kg) occurred at time points 5 and 8 h, but not 3 h after LPS injection. The antidepressant effect of the single LPS injection (100 μg/kg) lasted for at least 7 days, and 14 days after the single LPS injection, a repeated injection could still induce the stressed mice to develop an antidepressant phenotype. Furthermore, inhibition of microglia by minocycline or depletion of microglia by PLX3397 was found to prevent the antidepressant effect of the single LPS injection. These results suggest that reversing the decline of microglia in the dentate gyrus may be a potential strategy for the treatment of depression induced by harmful stress in adolescents.