title: NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
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.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9111, USA.
authors.forename: Anita E
authors.initials: AE
authors.lastname: Autry
authors.forename: Megumi
authors.initials: M
authors.lastname: Adachi
authors.forename: Elena
authors.initials: E
authors.lastname: Nosyreva
authors.forename: Elisa S
authors.initials: ES
authors.lastname: Na
authors.forename: Maarten F
authors.initials: MF
authors.lastname: Los
authors.forename: Peng-fei
authors.initials: PF
authors.lastname: Cheng
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Monteggia
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012146:Rest / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D000092864:Suicide Prevention
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D054736:Elongation Factor 2 Kinase