Essential roles of neuropeptide VGF regulated TrkB/mTOR/BICC1 signaling and phosphorylation of AMPA receptor subunit GluA1 in the rapid antidepressant-like actions of ketamine in mice.
Mengxin Shen, Dan Lv, Xu Liu, Shuting Li, Yaping Chen, Yanhua Zhang, Zhen Wang, Chuang Wang
Brain Research Bulletin October 2018 DOI: 10.1016/j.brainresbull.2018.10.004 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Mice subjected to chronic social defeat stress (CSDS), with lentiviral VGF knockdown in the prefrontal cortex |
| Intervention | Ketamine |
| Measures | Open field test, forced swim test, sucrose preference test |
| Topics | Ketamine Esketamine |
| Keywords | Bicc1 Trkb Vgf Mtor |
| Key findings | A single ketamine dose reversed CSDS-induced depression-like behaviors and the associated decrease in prefrontal cortex VGF in mice. Lentiviral knockdown of VGF increased immobility and decreased sucrose preference, effects ketamine did not improve, and blocked ketamine's regulation of TrkB/mTOR/BICC1 signaling and GluA1 Ser845 phosphorylation. The authors conclude that ketamine's rapid antidepressant-like actions require VGF. |
Abstract
Previous studies have suggested that rapid reductions in depression-like behaviors are observed in response to sub-anesthetic-doses of ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist. Neuropeptide VGF (non-acronymic) is a critical effector of depression-like behaviors and is thought to be involved in the antidepressant actions of ketamine that have been demonstrated. However, the mechanism underlying the involvement of VGF in the anti-depressant action of ketamine remains unclear. We found that single dose ketamine treatment reversed CSDS-induced depression-like behaviors and decrease of VGF in the PFC of mice. To investigate the involvement of VGF in the antidepressant-like effects of ketamine, a lentivirus vector for VGF was constructed to knockdown the expression of VGF in the prefrontal cortex (PFC) of mice. The biochemical and behavioral effects of this VGF knockdown were examined, using the open field, forced swim, and sucrose preference tests. Our results show that knockdown of VGF increased the immobility time and decreased the sucrose preference in mice. These effects were not improved by ketamine administration. In addition, we found that knockdown of VGF significantly decreased the expression of phosphorylation of tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 Ser845 and increased the expression of bicaudal C homolog 1 (BICC1) in the mouse PFC, and blocked the regulation of TrkB/mTOR/BICC1 signaling and GluA1 phosphorylation by ketamine. Our results indicate that the rapid onset antidepressant-like actions of ketamine require VGF to regulate TrkB/mTOR/BICC1 signaling and AMPA receptor GluA1 phosphorylation.