AMPK activation improves depression-like symptoms in olfactory bulbectomized mice by regulating microglia M1/M2 polarization in the hippocampus

Several studies have reported that the activation of adenosine monophosphate-activated protein kinase (AMPK) in the central nervous system is involved in antidepressant-like effects. We recently demonstrated that AMPK activators like 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleotide (AICAR) and liver hydrolysate containing an AMPK active ingredient can prevent depression-like behaviors in animal models of depression through enhanced cell proliferation in the hippocampal dentate gyrus (DG). However, it remains unclear whether microglia are involved in the antidepressant effects of AICAR in olfactory bulbectomized (OBX) mice, which is a useful animal model of depression. Therefore, in this study, we aimed to determine the mechanism of action of AICAR in OBX mice through various behavioral tests and immunohistochemical test. OBX mice exhibited depression-like behaviors in the tail suspension test (TST), forced swimming test (FST), sucrose splash test (SST), and sucrose preference test (SPT). Immunohistochemical studies revealed decreased hippocampal neuronal cell survival and an imbalance in microglial M1/M2 polarization: increased M1-like phenotype and decreased M2-like phenotype. However, AICAR treatment for 3 weeks improved the OBX-induced prolonged immobility in the TST and FST and decreased grooming time and sucrose intake rate in the SST and SPT, respectively. Chronic AICAR administration also ameliorated the reduction in hippocampal neuronal cell survival and the imbalance in microglia polarization. Our results indicate that activated AMPK improves depression-like behavior by neuroprotection via the regulation of microglial polarity. Thus, AMPK activation offers potential therapeutic avenues for developing novel treatment strategies for neuropsychiatric disorders such as depression.