Stimulation of microglia leads to a rapid antidepressant effect by triggering astrocytic P2Y1Rs and promoting BDNF-mediated neurogenesis in the hippocampus

Reversing the decline of microglia in the dentate gyrus of stressed animals has antidepressant effects, but the molecular mechanisms are unclear. Since microglia normally interact with astrocytes and astrocytic purinergic 2Y1 receptor (P2Y1R) signaling plays an important role in regulating cellular crosstalk, we hypothesize that astrocytic P2Y1R signaling may mediate the antidepressant effects of microglia stimulation. Our results showed that a single injection of low-dose lipopolysaccharide (LPS) (100 μg/kg) elicited rapid antidepressant effects and a significant increase in adenosine triphosphate (ATP) levels in the dentate gyrus in chronically stressed mice, and that these effects of LPS were abolished by chemogenetic inhibition of microglia. Depletion of endogenous ATP, non-specific antagonization of purinergic receptors, or specific inhibition of P2Y1Rs, but not other purinergic receptors, by MRS2179 in the hippocampus abolished the antidepressant effects of low-dose LPS. Conditional gene knockout data showed that the antidepressant effect of low-dose LPS could not be observed in mice lacking P2Y1Rs in astrocytes but not in forebrain neurons. Chemogenetic inhibition of microglia in the dentate gyrus, specific deletion of P2Y1Rs in astrocytes and the absence of ATP abolished the increase in doublecortin (DCX)⁺ cells and brain-derived neurotrophic factor (BDNF) induced by a low dose of LPS in the dentate gyrus of stressed mice, and infusion of BDNF antibodies into the hippocampus simultaneously abolished the pro-neurogenesis and antidepressant effects of microglia stimulation in stressed mice. Taken together, these results suggest that ATP signaling mobilized by microglia stimulation has an antidepressant effect by triggering astrocytic P2Y1R-dependent synthesis of BDNF.