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. 2021 Feb;590(7845):315-319.
doi: 10.1038/s41586-020-03047-0. Epub 2020 Dec 16.

Antidepressant actions of ketamine engage cell-specific translation via eIF4E

Argel Aguilar-Valles  1   2   3 , Danilo De Gregorio  4   5 , Edna Matta-Camacho  4   6 , Mohammad J Eslamizade  4   7 , Abdessattar Khlaifia  7 , Agnieszka Skaleka  4 , Martha Lopez-Canul  5 , Angelica Torres-Berrio  8 , Sara Bermudez  4 , Gareth M Rurak  6 , Stephanie Simard  6 , Natalina Salmaso  6 , Gabriella Gobbi  5 , Jean-Claude Lacaille  7 , Nahum Sonenberg  9
Affiliations

Antidepressant actions of ketamine engage cell-specific translation via eIF4E

Argel Aguilar-Valles et al. Nature. 2021 Feb.

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.

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