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
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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.
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- 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).
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