Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine.
Chinnakkaruppan Adaikkan, Elham Taha, Iliana Barrera, Orit David, Kobi Rosenblum
Biological Psychiatry July 1, 2018 DOI: 10.1016/j.biopsych.2017.11.028 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Wild-type C57BL/6 mice and eEF2K knockout mice |
| Interventions | Ketamine tatCN21 |
| Measures | forced swim test, tail suspension test, novelty suppressed feeding test |
| Topics | Ketamine Esketamine |
| Keywords | Camkii Glua1 Protein synthesis Eef2 kinase Tatcn21 |
| Key findings | Knocking out eEF2K eliminated eEF2 phosphorylation at threonine 56, increased protein synthesis, and made mice resistant to ketamine's antidepressant effects. Ketamine caused transient CaMKII inhibition (pT305, 10-20 minutes) concurrent with eEF2K-dependent protein synthesis, followed by CaMKII activation (pT286) that regulated delayed GluA1 induction at 24 hours. The CaMKII inhibitor tatCN21 increased protein synthesis and induced behavioral resistance to ketamine. |
Abstract
Ketamine is an N-methyl-D-aspartate receptor antagonist, which on administration produces fast-acting antidepressant responses in patients with major depressive disorder. Yet, the mechanism underlying the antidepressant action of ketamine remains unclear. To unravel the mechanism of action of ketamine, we treated wild-type C57BL/6 mice with calcium/calmodulin-dependent protein kinase II (CaMKII) specific inhibitor tatCN21 peptide. We also used eukaryotic elongation factor 2 kinase (eEF2K) (also known as CaMKIII) knockout mice. We analyzed the effects biochemically and behaviorally, using the forced swim, tail suspension, and novelty suppressed feeding tests. Consistent with the literature, one of the major pathways mediating the antidepressant action of ketamine was reduction of phosphorylation of eEF2 via eEF2K. Specifically, knocking out eEF2K in mice eliminated phosphorylation of eEF2 at threonine at position 56, resulting in increased protein synthesis, and made mice resistant both biochemically and behaviorally to the antidepressant effects of ketamine. In addition, administration of ketamine led to differential regulation of CaMKII function, manifested as autoinhibition (pT305 phosphorylation) followed by autoactivation (pT286) of CaMKIIα in the hippocampus and cortex. The inhibition phase of CaMKII, which lasted 10 to 20 minutes after administration of ketamine, occurred concurrently with eEF2K-dependent increased protein synthesis. Moreover, ketamine administration-dependent delayed induction of GluA1 (24 hours) was regulated by the activation of CaMKII. Importantly, systemic administration of the CaMKII inhibitor tatCN21 increased global protein synthesis and induced behavioral resistance to ketamine. Our data suggest that drugs that selectively target CaMKs and regulate protein synthesis offer novel strategies for treatment of major depressive disorder.
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 14
- Ketamine and the Future of Rapid-Acting Antidepressants Annual Review of Clinical Psychology February 9, 2021
- Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant Frontiers in Pharmacology July 7, 2022
- Molecular mechanisms of rapid-acting antidepressants: New perspectives for developing antidepressants Pharmacological Research June 26, 2023
- Hippocampal PACAP signaling activation triggers a rapid antidepressant response. Military Medical Research July 23, 2024
- The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry July 7, 2025
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Cites 12
- 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
- Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
and 7 more in the library