Journal Article

Antidepressant actions of ketamine engage cell-specific translation via eIF4E

De Gregorio, Danilo, Lopez-Canul, Martha, Bermudez, Sara, Salmaso, Natalina, Eslamizade, Mohammad J., Khlaifia, Abdessattar, Torres-Berrio, Angelica, Rurak, Gareth M., Gobbi, Gabriella, Aguilar-Valles, Argel, Lacaille, Jean-Claude, Sonenberg, Nahum, Matta-Camacho, Edna, Skaleka, Agnieszka, Simard, Stephanie

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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