Zymosan A produces a rapid and sustained antidepressant effect in chronically stressed mice by stimulating hippocampal microglia

Recent studies had reported that compounds that stimulate microglia could be developed as potential drugs for the treatment of depression due to their reversal effect on depression-like behaviors in chronically stressed mice. Zymosan A is a cell wall preparation of Saccharomyces cerevisiae composed of β-glucans. Based on its immuno-stimulatory activities, we hypothesized that zymosan A might have a therapeutic effect on depression. Our results showed that a single injection of zymosan A 5 h before behavioral tests at a dose of 1 or 2 mg/kg, but not at a dose of 0.5 mg/kg, reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in mice in the tail suspension test, forced swimming test, and sucrose preference test. Time-dependent analysis showed that the antidepressant effect of zymosan A (2 mg/kg) in CUS mice became statistically significant at 5 and 8 h, but not at 3 h, and persisted for at least 7 days. Fourteen days after a single injection of zymosan A, no antidepressant effect was observed anymore. However, the disappeared antidepressant effect of zymosan A was restored by a second zymosan A injection (2 mg/kg, 5 h) 14 days after the first zymosan A injection. Stimulation of microglia was essential for the antidepressant effect of zymosan A because pre-inhibition of microglia by minocycline or pre-depletion of microglia by PLX3397 prevented the antidepressant effect of zymosan A. Based on these effects of zymosan A, zymosan A administration could be developed as a new strategy for the treatment of depression.