title: PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13.
abstract: BACKGROUND
  VGF (nonacryonimic) and phosphatidylinositol 3-kinase (PI3K)/AKT (also known as protein kinase B, PKB)/mammalian target of rapamycin (mTOR) signaling play pivotal roles in depression. However, whether phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF participates in rapid-acting antidepressant-like actions of GLYX-13 is unclear.
  
  
  METHODS
  Herein, we evaluated the effects of acute treatment of GLYX-13 (0.5, 5, and 10mg/kg, i.p.) in the forced swim test. In addition, we assessed whether the acute treatment with GLYX-13 reverses the depressive-like behaviors induced by chronic unpredictable mild stress. Furthermore, we determined whether the Vgf knockdown in hippocampus of mice blocks the effects of GLYX-13. Moreover, we also demonstrated the effects of intra-hippocampus infusion of LY294002 (10 nmol/side), a specific phosphatidylinositol 3-kinase inhibitor prior to the treatment of GLYX-13 in the forced swim test. Lastly, whether alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mTOR activation involves in the antidepressant-like effects of GLYX-13 was examined.
  
  
  RESULTS
  Our results shown that GLYX-13 dose-dependently reversed the depressive-like behaviors in forced swim test. Additionally, GLYX-13 significantly reversed the downregulation of phosphorylation of AKT, mTOR, and eukaryotic elongation factor 2 as well as VGF induced by chronic unpredictable mild stress in hippocampus. Further, Vgf knockdown in hippocampus of mice significantly blocked the rapid-acting antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Moreover, intra-hippocampus infusion of LY294002 significantly abolished the antidepressant-like effects and upregulation on phosphatidylinositol 3-kinase/AKT/mTOR/VGF signaling of GLYX-13. Finally, antidepressant-like effects of GLYX-13 required AMPA receptor and mTOR activation, as evidenced by the ability of NBQX and rapamycin to block the effects of GLYX-13, respectively.
  
  
  CONCLUSIONS
  Our results suggest that phosphatidylinositol 3-kinase/AKT/mTOR signaling-mediated VGF in hippocampus may be involved in the antidepressant-like effects of GLYX-13.
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China. wangchuang@nbu.edu.cn wanglovechuang@163.com.
authors.forename: Chuang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Zhancheng
authors.initials: Z
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Chenli
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, Zhejiang, PR China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology; D009414:Nerve Growth Factors; D009479:Neuropeptides / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000150:complications; D013550:Swimming / Q000523:psychology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D002867:Chromones; D054736:Elongation Factor 2 Kinase; D004791:Enzyme Inhibitors; D009025:Morpholines; D009414:Nerve Growth Factors; D009479:Neuropeptides; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C512697:Vgf protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507283:GLYX-13 peptide; C546842:MTOR protein, human
keywords: GLYX-13; PI3K/AKT/mTOR signaling; VGF (nonacryonimic); depression