The immunoregulator β-glucan produces antidepressant effects through microglia-mobilized astrocytic P2Y1R-BDNF signaling in the dentate gyrus.

β-Glucan, a polysaccharide from Saccharomyces cerevisiae with immunomodulatory activities that may not trigger pro-inflammatory responses in microglia, has been reported to show rapid antidepressant effects in chronically stressed animals by restoring microglial function in the dentate gyrus. However, the mechanisms underlying this effect of β-glucan are still largely unclear. Considering the importance of astrocytic purinergic 2Y1 receptors (P2Y1Rs) and brain-derived neurotrophic factor (BDNF) in the antidepressant effects of microglial stimulation, we hypothesize that β-glucan produces antidepressant effects by mobilizing astrocytic P2Y1R-triggered BDNF signaling in the hippocampus. Our results showed that a single injection of β-glucan (20 mg/kg) reversed chronic unpredictable stress (CUS)-induced depression-like behavior and decreased adenosine triphosphate (ATP) levels in the dentate gyrus of mice, which was abolished by chemogenetic inhibition of microglia. Degradation of endogenous ATP by apyrase, non-specific antagonism of purinergic receptors by suramin, specific antagonism of P2Y1Rs in the hippocampus or selective deletion of P2Y1R in astrocytes was able to abolish the antidepressant effect of β-glucan. In addition, the β-glucan-induced increase of BDNF in the dentate gyrus of CUS mice was abolished by chemogenetic inhibition of microglia, selective deletion of P2Y1Rs in astrocytes or depletion of endogenous ATP in the hippocampus. Further analysis showed that antagonism of BDNF signaling in the hippocampus abolished the antidepressant effect of β-glucan. These results suggest that ATP-triggered astrocytic P2Y1R signaling may mediate the antidepressant effect of β-glucan by promoting BDNF production in the hippocampus.