NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
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Open Access
- 15 June 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 475 (7354), 91-95
- https://doi.org/10.1038/nature10130
Abstract
Antidepressants such as selective serotonin re-uptake inhibitors can take months to take effect, but small doses of ketamine, a glutamatergic N-methyl-D-aspartate receptor (NMDAR) agonist, can have antidepressant effects within hours. The antidepressant mechanism of ketamine is not well understood. Work in mice shows that antidepressant-like effects of ketamine depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). Ketamine-mediated NMDAR blockade deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and de-suppression of BDNF translation. These findings raise the possibility of this pathway as a therapeutic target for fast-acting antidepressants. Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear1,2,3. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks1,2,3, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients3. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.Keywords
This publication has 35 references indexed in Scilit:
- Local Presynaptic Activity Gates Homeostatic Changes in Presynaptic Function Driven by Dendritic BDNF SynthesisNeuron, 2010
- Postsynaptic GluA1 enables acute retrograde enhancement of presynaptic function to coordinate adaptation to synaptic inactivityProceedings of the National Academy of Sciences of the United States of America, 2010
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA AntagonistsScience, 2010
- Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant DepressionBiological Psychiatry, 2009
- NMDA Receptor Activation by Spontaneous Glutamatergic NeurotransmissionJournal of Neurophysiology, 2009
- Spontaneous and Evoked Glutamate Release Activates Two Populations of NMDA Receptors with Limited OverlapJournal of Neuroscience, 2008
- Elongation Factor 2 and Fragile X Mental Retardation Protein Control the Dynamic Translation of Arc/Arg3.1 Essential for mGluR-LTDNeuron, 2008
- Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant EfficacyBiological Psychiatry, 2008
- Postsynaptic Decoding of Neural Activity: eEF2 as a Biochemical Sensor Coupling Miniature Synaptic Transmission to Local Protein SynthesisNeuron, 2007
- Actinomycin d blocks the reducing effect of dexamethasone on amphetamine and cocaine hypermotility in miceGeneral Pharmacology: The Vascular System, 1996