Intranasal Monophosphoryl Lipid a Administration Ameliorates depression-like Behavior in Chronically Stressed Mice Through Stimulation of Microglia.

We and others have reported that systematic stimulation of the central innate immune system by a low dose of lipopolysaccharide (LPS) can improve depression-like behavior in chronically stressed animals. However, it is unclear whether similar stimulation by intranasal administration could improve depression-like behavior in animals. We investigated this question using monophosphoryl lipid A (MPL), a derivative of LPS that lacks the adverse effects of LPS but is still immuno-stimulatory. We found that a single intranasal administration of MPL at a dose of 10 or 20 µg/mouse, but not at a dose of 5 µg/mouse, ameliorated chronic unpredictable stress (CUS)-induced depression-like behavior in mice, as evidenced by the decrease in immobility time in tail suspension test and forced swimming test and the increase in sucrose intake in sucrose preference test. In the time-dependent analysis, the antidepressant-like effect of a single intranasal MPL administration (20 µg/mouse) was observed 5 and 8 h but not 3 h after drug administration and persisted for at least 7 days. Fourteen days after the first intranasal MPL administration, a second intranasal MPL administration (20 µg/mouse) still showed an antidepressant-like effect. The innate immune response mediated by microglia might mediate the antidepressant-like effect of intranasal MPL administration, because both inhibition of microglial activation by pretreatment with minocycline and depletion of microglia by pretreatment with PLX3397 prevented the antidepressant-like effect of intranasal MPL administration. These results suggest that intranasal administration of MPL can produce significant antidepressant-like effects in animals under chronic stress conditions via stimulation of microglia.

Microglial stimulation triggered by intranasal lipopolysaccharide administration produces antidepressant-like effect through ERK1/2-mediated BDNF synthesis in the hippocampus.

We recently reported that reversing the chronic stress-induced decline of microglia in the dentate gyrus (DG) of the hippocampus by intraperitoneal injection of a low dose of lipopolysaccharide (LPS) ameliorated depression-like behavior in chronically stressed mice. In this study, we found that a single intranasal administration of LPS dose-dependently improved depression-like behavior in mice treated with chronic unpredictable stress (CUS), as evidenced by the reduction of immobility time in the tail suspension test (TST) and forced swimming test (FST) and by the increase of sucrose uptake in the sucrose preference test (SPT). The antidepressant effects of intranasal administration of LPS could be abolished by inhibition of brain-derived neurotrophic factor (BDNF) signaling by infusion of an anti-BDNF antibody, by knock-in of the mutant BDNF Val68Met allele, or by the BDNF receptor antagonist K252a. In addition, intranasal administration of LPS was found to exert antidepressant effects in a BDNF-dependent manner via promotion of BDNF synthesis mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling in DG. Inhibition of microglia by minocycline or depletion of microglia by PLX3397 was able to abolish the reversal effect of intranasal LPS administration on CUS-induced depression-like behaviors as well as the CUS-induced decrease in phospho-ERK1/2 and BDNF protein levels in DG. These results demonstrate that stimulation of hippocampal microglia by intranasal LPS administration can induce antidepressant effects via ERK1/2-dependent synthesis of BDNF protein, providing hope for the development of new strategies for the treatment of depression.