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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 8
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Ketamine and its metabolites: Potential as novel treatments for depression. Neuropharmacology October 1, 2022
- Rodent ketamine depression-related research: Finding patterns in a literature of variability Behavioural Brain Research August 13, 2019
- Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A systematic review of animal models of depression. Neuroscience & Biobehavioral Reviews September 1, 2024
- Decoding the molecular network communication mechanism of ketamine's antidepressant effects. Psychopharmacology March 16, 2026
and 3 more in the library
Cites 10
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
and 5 more in the library