Hippocampal AMPK activation suppresses depressive-like behavior in olfactory bulbectomized mice

[Speaker] Takayo Odaira:1
[Co-author] Osamu Nakagawasai:1, Wataru Nemoto:1, Kohei Takahashi:1, Wakana Sakuma:1, Ryotaro Ono:1, Koichi Tan-No:1
1:Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan

[Background] AMP-activated protein kinase (AMPK) is a serine-threonine kinase and plays an important role in the regulation of whole body energy metabolism. Recent studies have suggested that physical exercise ameliorate depressive-like behaviors via AMPK activation in both rodents and patients. However, roles of AMPK on emotional function are unclear. In this study, we examined the effects and underlying mechanisms of 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK, on depressive-like behavior in olfactory bulbectomized (OBX) mice, an animal model of depression.
[Methods] Adult male ddY mice were subjected to bilateral olfactory bulbectomy or sham surgery. AICAR treatment began either on the 7th day or the 14th day after the surgery. Depressive-like behavior was evaluated by tail-suspension test (TST) on the 21st day after surgery. The expression of hippocampal phosphorylation of AMPK, protein kinase C (PKC) ζ, cAMP response element-binding protein (CREB) and brain derived neurothrophic factor (BDNF) were assessed by Western blotting. Neurogenesis in the hippocampal dentate gyrus was measured by immunohistochemical method.
[Results] Subchronic but not acute treatment with AICAR suppressed the prolonged immobility time in OBX mice. Phosphorylated AMPK, PKCζ and CREB, and expression level of BDNF in OBX mice were increased by subchronic administration of AICAR. Immunohistchemical analysis showed that the neurogenesis in the dentate gyrus of hippocampus significantly decreased in OBX mice whereas they increased after subchronic treatment with AICAR.
[Conclusions] These data indicate that AMPK activation produced antidepressant effect and this effect is characterized by hippocampal neurogenesis potentially activated through PKCζ/CREB/BDNF signaling pathways. The present study suggests that AMPK activation agent may become a new therapeutic target of depression.
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