Antidepressant actions of ketamine engage cell-specific translation via eIF4E

• Published in: Nature (London) 2021-02, Vol.590 (7845), p.315-319
• Main Authors: Aguilar-Valles, Argel, De Gregorio, Danilo, Matta-Camacho, Edna, Eslamizade, Mohammad J., Khlaifia, Abdessattar, Skaleka, Agnieszka, Lopez-Canul, Martha, Torres-Berrio, Angelica, Bermudez, Sara, Rurak, Gareth M., Simard, Stephanie, Salmaso, Natalina, Gobbi, Gabriella, Lacaille, Jean-Claude, Sonenberg, Nahum
• Format: Article
• Language: English
• Subjects: 13/51; 631/378/1689/1414; 631/378/340; 64; 64/60; 9/30; 9/74; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antidepressants; Antidepressive Agents - pharmacology; Binding proteins; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Depression, Mental; Depressive Disorder, Major - drug therapy; Dosage and administration; Drug therapy; Eukaryotic Initiation Factor-4E - metabolism; Eukaryotic Initiation Factors - genetics; Eukaryotic Initiation Factors - metabolism; Excitatory Postsynaptic Potentials - drug effects; Gene deletion; Glutamate receptors; Health aspects; Hippocampal plasticity; Hippocampus; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Humanities and Social Sciences; Inactivation; Inhibitory Postsynaptic Potentials - drug effects; Initiation factor eIF-4E; Interneurons - drug effects; Interneurons - metabolism; Ketamine; Ketamine - analogs & derivatives; Ketamine - metabolism; Ketamine - pharmacology; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mental depression; Metabolites; Mice; Mimicry; mRNA; multidisciplinary; Mutation; N-Methyl-D-aspartic acid receptors; Neural Inhibition - drug effects; Neural Inhibition - genetics; Neurons; Neurons - classification; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurotransmission; Phosphorylation; Protein Biosynthesis - drug effects; Protein synthesis; Proteins; Pyramidal Cells - drug effects; Pyramidal Cells - metabolism; Rodents; Science; Science (multidisciplinary); Serotonin; Serotonin uptake inhibitors; Synaptic plasticity; Synaptic Transmission - drug effects; Translation initiation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-03047-0

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 antagonist 2 , 3 , provide rapid and long-lasting antidepressant effects in these patients 4 – 6 , but the molecular mechanism of these effects remains unclear 7 , 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 kinase 10 , 11 . mTORC1 controls various neuronal functions 12 , 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 cortex 8 , 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. The antidepressant-like effects of ketamine in mice depend on the expression of specific eIF4E-binding proteins in excitatory and inhibitory neurons.