title: Protein kinase Mζ is involved in the modulatory effect of fluoxetine on hippocampal neurogenesis in vitro.
abstract: The efficacy of chronic selective serotonin reuptake inhibitors (SSRIs) on depression is paralleled by the recovery of deficits in hippocampal neurogenesis related to sustained stress and elevated glucocorticoids. Previous studies have shown that atypical protein kinase C (aPKC) is implicated in the regulation of neurogenesis and the antidepressant response. Whether the specific aPKC isoforms (PKCζ, PKMζ and PKCι) are involved in SSRI-induced hippocampal neurogenesis and the underlying mechanisms is unknown. The present study shows that PKMζ and PKCι but not PKCζ are expressed in rat embryonic hippocampal neural stem cells (NSCs), whereas PKMζ but not PKCι expression is increased by the SSRI fluoxetine both in the absence and presence of the glucocorticoid receptor agonist dexamethasone. PKMζ shRNA significantly decreased neuronal proliferation and neuron-oriented differentiation, increased NSC apoptosis, and blocked the stimulatory effect of fluoxetine on NSC neurogenesis. Fluoxetine significantly increased PKMζ expression in hippocampal NSCs in a 5-hydroxytryptamine-1A (5-HT1A) receptor-dependent manner in both the absence and presence of dexamethasone. The PKMζ peptide blocker ZIP and MEK inhibitor U0126 significantly inhibited the increase in extracellular signal-regulated kinase 1/2 and cyclic adenosine monophosphate response element binding protein phosphorylation in the mitogen-activated protein kinase (MAPK) pathway and hippocampal NSC neurogenesis in response to fluoxetine and the 5-HT1A receptor agonist 8-OH DPAT. Collectively, our results suggest that the SSRI ﬂuoxetine increases hippocampal NSC neurogenesis via a PKMζ-mediated mechanism that links 5-HT1A receptor activation with the phosphorylation of the downstream MAPK signaling pathway.
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Ying Xin
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Xiang Rong
authors.initials: XR
authors.lastname: Zhang
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Zhi Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Guang Jun
authors.initials: GJ
authors.lastname: Xi
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine,Southeast University,Nanjing,China.
authors.forename: Yan Juan
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D003907:Dexamethasone; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat