PI3K/AKT/mTOR signaling-mediated neuropeptide VGF in the hippocampus of mice is involved in the rapid onset antidepressant-like effects of GLYX-13

Int J Neuropsychopharmacol. 2014 Dec 25;18(5):pyu110. doi: 10.1093/ijnp/pyu110.

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.

Keywords: GLYX-13; PI3K/AKT/mTOR signaling; VGF (nonacryonimic); depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Chromones / pharmacology
  • Depression / drug therapy
  • Depression / metabolism
  • Depression / psychology
  • Elongation Factor 2 Kinase / metabolism
  • Enzyme Inhibitors / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Morpholines / pharmacology
  • Nerve Growth Factors
  • Neuropeptides / metabolism*
  • Oligopeptides / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects
  • Stress, Psychological / complications
  • Swimming / psychology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Antidepressive Agents
  • Chromones
  • Enzyme Inhibitors
  • Morpholines
  • Nerve Growth Factors
  • Neuropeptides
  • Oligopeptides
  • Phosphoinositide-3 Kinase Inhibitors
  • Vgf protein, mouse
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • GLYX-13 peptide
  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Elongation Factor 2 Kinase