Antidepressant actions of ketamine engage cell-specific translation via eIF4E

Argel Aguilar-Valles (), Danilo De Gregorio, Edna Matta-Camacho, Mohammad J. Eslamizade, Abdessattar Khlaifia, Agnieszka Skaleka, Martha Lopez-Canul, Angelica Torres-Berrio, Sara Bermudez, Gareth M. Rurak, Stephanie Simard, Natalina Salmaso, Gabriella Gobbi, Jean-Claude Lacaille and Nahum Sonenberg ()
Additional contact information
Argel Aguilar-Valles: McGill University
Danilo De Gregorio: McGill University
Edna Matta-Camacho: McGill University
Mohammad J. Eslamizade: McGill University
Abdessattar Khlaifia: Université de Montréal
Agnieszka Skaleka: McGill University
Martha Lopez-Canul: McGill University
Angelica Torres-Berrio: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Sara Bermudez: McGill University
Gareth M. Rurak: Carleton University
Stephanie Simard: Carleton University
Natalina Salmaso: Carleton University
Gabriella Gobbi: McGill University
Jean-Claude Lacaille: Université de Montréal
Nahum Sonenberg: McGill University

Nature, 2021, vol. 590, issue 7845, 315-319

Abstract: Abstract Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors)1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist2,3, provide rapid and long-lasting antidepressant effects in these patients4–6, but the molecular mechanism of these effects remains unclear7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK)9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase10,11. mTORC1 controls various neuronal functions12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs)13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1–4E-BP signalling in pyramidal excitatory cells of the cortex8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-020-03047-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:590:y:2021:i:7845:d:10.1038_s41586-020-03047-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-03047-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().