Fluoxetine regulates neurogenesis in vitro through modulation of gsk-3b/b-catenin signaling

Abstract

Background: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3b)/b-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. Methods: The aim of this study was to determine whether GSK-3b/b-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine's regulation of GSK-3b/b-catenin signaling pathway were also examined. Results: Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3b and increasing the level of nuclear b-catenin. The overexpression of a stabilized b-catenin protein (N89 b-catenin) significantly increased NPC proliferation, while inhibition of b-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3b and nuclear b-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. Conclusions: The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3b/b-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation.