Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
Our data suggest that drugs that selectively target CaMKs and regulate protein synthesis
offer novel strategies for treatment of major depressive disorder.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The molecular neurobiology of depression.Nature. 2008; 455: 894-902
- Selective serotonin reuptake inhibitors versus tricyclic antidepressants: A meta-analysis of efficacy and tolerability.J Affect Disord. 2000; 58: 19-36
- Selective serotonin reuptake inhibitors in childhood depression: Systematic review of published versus unpublished data.Lancet. 2004; 363: 1341-1345
- Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: Children versus adolescents.J Child Adolesc Psychopharmacol. 2006; 16: 159-169
- Antidepressant drug effects and depression severity: A patient-level meta-analysis.JAMA. 2010; 303: 47-53
- Effects of ketamine on explicit and implicit suicidal cognition: A randomized controlled trial in treatment-resistant depression.Depress Anxiety. 2014; 31: 335-343
- Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial.Am J Psychiatry. 2013; 170: 1134-1142
- Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression.Biol Psychiatry. 2013; 74: 250-256
- Antidepressant mechanism of ketamine: Perspective from preclinical studies.Front Neurosci. 2015; 9: 249
- Replication of ketamine’s antidepressant efficacy in bipolar depression: A randomized controlled add-on trial.Biol Psychiatry. 2012; 71: 939-946
- The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine.Biol Psychiatry. 2013; 73: 1199-1203
- Antidepressant actions of ketamine: from molecular mechanisms to clinical practice.Curr Opin Neurobiol. 2015; 30: 139-143
- Ketamine infusions for treatment resistant depression: A series of 28 patients treated weekly or twice weekly in an ECT clinic.J Psychopharmacol. 2014; 28: 536-544
- Antidepressant effects of ketamine in depressed patients.Biol Psychiatry. 2000; 47: 351-354
- NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism.Behav Brain Res. 2015; 287: 89-95
- Synaptic mechanisms underlying rapid antidepressant action of ketamine.Am J Psychiatry. 2012; 169: 1150-1156
- How does ketamine elicit a rapid antidepressant response?.Curr Opin Pharmacol. 2015; 20: 35-39
- Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy.Biol Psychiatry. 2008; 63: 642-649
- BDNF—a key transducer of antidepressant effects.Neuropharmacology. 2016; 102: 72-79
- Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication.Biol Psychiatry. 2001; 50: 260-265
- Signaling pathways underlying the pathophysiology and treatment of depression: Novel mechanisms for rapid-acting agents.Trends Neurosci. 2012; 35: 47-56
- GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine.Elife. 2014; 3e03581
- Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex.Biol Psychiatry. 2012; 71: 996-1005
- Pushing the threshold: How NMDAR antagonists induce homeostasis through protein synthesis to remedy depression.Brain Res. 2016; 1647: 94-104
- Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.Eur Psychiatry. 2014; 29: 419-423
- Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test.Ups J Med Sci. 2013; 118: 3-8
- BDNF release is required for the behavioral actions of ketamine.Int J Neuropsychopharmacol. 2014; 18
- Acute suppression of spontaneous neurotransmission drives synaptic potentiation.J Neurosci. 2013; 33: 6990-7002
- NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.Nature. 2011; 475: 91-95
- Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses.Proc Natl Acad Sci U S A. 2014; 111: 8649-8654
- eEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures.Cerebral Cortex. 2016; 27: 2226-2248
- A molecular mechanism underlying gustatory memory trace for an association in the insular cortex.Elife. 2015; 4e07582
- CaMKII “autonomy” is required for initiating but not for maintaining neuronal long-term information storage.J Neurosci. 2010; 30: 8214-8220
- Regulatory mechanisms of AMPA receptors in synaptic plasticity.Nat Rev Neurosci. 2007; 8: 101-113
- Driving AMPA receptors into synapses by LTP and CaMKII: Requirement for GluR1 and PDZ domain interaction.Science. 2000; 287: 2262-2267
- Mechanism of Ca2/calmodulin-dependent kinase II regulation of AMPA receptor gating.Nat Neurosci. 2011; 14: 727-735
- Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength.J Neurosci. 2011; 31: 9170-9178
- Interaction with the NMDA receptor locks CaMKII in an active conformation.Nature. 2001; 411: 801-805
- CaMKII binding to GluN2B is critical during memory consolidation.EMBO J. 2012; 31: 1203-1216
- The roles of protein kinases in learning and memory.Learn Mem. 2013; 20: 540-552
- Elongation factor 2 kinase is regulated by proline hydroxylation and protects cells during hypoxia.Mol Cell Biol. 2015; 35: 1788-1804
- Dual mechanism of a natural CaMKII inhibitor.Mol Biol Cell. 2007; 18: 5024-5033
- Effective post-insult neuroprotection by a novel Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor.J Biol Chem. 2010; 285: 20675-20682
- The tail suspension test.J Vis Exp. 2012; e3769
- Autonomous CaMKII activity as a drug target for histological and functional neuroprotection after resuscitation from cardiac arrest.Cell Rep. 2017; 18: 1109-1117
- The molecular basis of CaMKII function in synaptic and behavioural memory.Nat Rev Neurosci. 2002; 3: 175-190
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites.Nature. 2016; 533: 481-486
- Effects of CaMKII inhibitor tatCN21 on activity-dependent redistribution of CaMKII in hippocampal neurons.Neuroscience. 2013; 244: 188-196
- Mammalian target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model.Biol Psychiatry. 2018; 83: 18-28
- mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABA B R signaling.Neuropharmacology. 2013; 73: 192-203
- Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior.Proc Natl Acad Sci U S A. 2015; 112: 6188-6193
- mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.Science. 2010; 329: 959-964
- Ketamine and rapid-acting antidepressants: A window into a new neurobiology for mood disorder therapeutics.Annu Rev Med. 2015; 66: 509-523
- Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine.Sci Signal. 2016; 9: ra123
- Metabolic turnover of synaptic proteins: Kinetics, interdependencies and implications for synaptic maintenance.PloS One. 2013; 8e63191
- The roles of protein expression in synaptic plasticity and memory consolidation.Front Mol Neurosci. 2014; 7: 86
- ERK-dependent PSD-95 induction in the gustatory cortex is necessary for taste learning, but not retrieval.Nat Neurosci. 2008; 11: 1149-1151
- Practical application of the neuroregenerative properties of ketamine: Real world treatment experience.Neural Regen Res. 2016; 11: 195-200
- Antidepressant actions of ketamine versus hydroxynorketamine.Biol Psychiatry. 2017; 81: e65-e67
- Selective publication of antidepressant trials and its influence on apparent efficacy.N Engl J Med. 2008; 358: 252-260
- Mode of action of antidepressant drugs.Biochem Pharmacol. 1978; 27: 257-261
Article Info
Publication History
Published online: December 01, 2017
Accepted:
November 13,
2017
Received in revised form:
November 12,
2017
Received:
January 19,
2017
Footnotes
CA is currently affiliated with The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Identification
Copyright
© 2017 Society of Biological Psychiatry.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Hopes and Skepticism for Unraveling the Unique Mechanisms of Ketamine’s Rapid Onset Antidepressant Actions in Rodent ModelsBiological PsychiatryVol. 84Issue 1
- PreviewInterest in ketamine and other potentially rapidly acting antidepressant medications has increased dramatically over the past decade. Although work dating back to the early 1990s suggested that N-methyl-D-aspartate receptor–modulating drugs may generate antidepressant effects (1), major interest in this approach was truly ignited by the initial report of ketamine’s rapid-onset antidepressant action by Berman et al. in 2000 (2) and a second proof-of-concept study completed at the National Institute of Mental Health in 2006 (3).
- Full-Text
- Preview
