Nature (2020). https://doi.org/10.1038/s41467-019-13162-w
Argel Aguilar-Valles1,2,3,6 ✉, Danilo De Gregorio1,4, Edna Matta-Camacho1,3, Mohammad J. Eslamizade1,2, Abdessattar Khlaifia2, Agnieszka Skaleka1, Martha Lopez-Canul4, Angelica Torres-Berrio5, Sara Bermudez1, Gareth M. Rurak3, Stephanie Simard3, Natalina Salmaso3, Gabriella Gobbi4, Jean-Claude Lacaille2,6 & Nahum Sonenberg1,6
1Department of Biochemistry and Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada. 2Department of Neurosciences and Centre for Interdisciplinary Research on Brain and Learning, Université de Montréal, Montreal, Quebec, Canada. 3Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada. 4Department of Psychiatry, McGill University, Montreal, Quebec, Canada. 5Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6These authors jointly supervised this work: Argel Aguilar-Valles, Jean-Claude Lacaille, Nahum Sonenberg. ✉e-mail: firstname.lastname@example.org; email@example.com
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 noncompetitive 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 ketamineinduced 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.