title: Fluoxetine regulates neurogenesis in vitro through modulation of GSK-3β/β-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-3β)/β-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-3β/β-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-3β/β-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-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-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-3β and nuclear β-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-3β/β-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation.
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Jiaojie
authors.initials: J
authors.lastname: Hui
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Hoon
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Chang
authors.initials: C
authors.lastname: Tong
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Qilong
authors.initials: Q
authors.lastname: Ying
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Zaiwang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Xuqiang
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Guofeng
authors.initials: G
authors.lastname: Shi
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang).
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Critical Care Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs Hui and Yan); Department of Neurology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China (Drs J Zhang, Li, Mao, Shi, and Xi); Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, University of Southern California, Los Angeles, CA (Drs Kim, Tong, and Ying); Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, China (Dr Z Zhang). xiguangjun@163.com.
authors.forename: Guangjun
authors.initials: G
authors.lastname: Xi
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D008297:Male; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D005473:Fluoxetine; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017367:Selective Serotonin Reuptake Inhibitors; D051176:beta Catenin; C000605508:Gsk3b protein, rat
keywords: cell proliferation; fluoxetine; glycogen synthase kinase-3 beta; neural precursor cells; β-catenin