NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

Anita E. Autry, Megumi Adachi, Elena Nosyreva, Elisa S. Na, Maarten F. Los, Peng Fei Cheng, Ege T Kavalali, Lisa M Monteggia

Research output: Contribution to journalArticle

1033 Scopus citations

Abstract

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 unclear. 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 weeks, 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 patients. 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.

Original languageEnglish (US)
Pages (from-to)91-96
Number of pages6
JournalNature
Volume475
Issue number7354
DOIs
StatePublished - Jul 7 2011

ASJC Scopus subject areas

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    Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P. F., Kavalali, E. T., & Monteggia, L. M. (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature, 475(7354), 91-96. https://doi.org/10.1038/nature10130