Identification of a microglial activation-dependent antidepressant effect of amphotericin B liposome

Chronic stress-induced decline in microglia in the hippocampus is a newly hypothesized mechanism of depression, and reversal of this decline by microglial activators has been shown to suppress depression-like behaviors in mice. This suggests that activation of immune cells in the hippocampus may be a potential strategy for depression therapy. Since amphotericin B, an anti-fungal medication, is known to activate macrophages and microglia, we investigated whether conventional amphotericin B or its liposomal form displays antidepressant activity. Our results showed that both amphotericin B and its liposomal form at various doses induced obvious depression-like behaviors in naïve mice, likely owing to increased serum interleukin-6 (IL-6) and IL-1β levels. However, under stressed conditions, amphotericin B liposome, but not amphotericin B itself, reversed chronic unpredictable stress (CUS)-induced increase in immobility time in the tail suspension test and forced swim test as well as CUS-induced decrease in sucrose intake in the sucrose preference test and the time spent in the center region of the open field test in a dose-dependent manner. Immunofluorescence analysis showed that amphotericin B liposome reversed the CUS-induced decline in dentate gyrus (DG) microglia, and inhibition or ablation of microglia in the hippocampus by minocycline (40 mg/kg) or PLX3397 pre-treatment (290 mg/kg) abrogated the antidepressant effect of the amphotericin B liposome in CUS-treated mice. These results not only identify a novel pharmacological effect of amphotericin B liposome, but further support the notion that microglial activation in the hippocampus is a potential strategy for depression therapy.