Antidepressant actions of ketamine engage cell-specific translation via eIF4E
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...
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Veröffentlicht in: | Nature (London) 2021-02, Vol.590 (7845), p.315-319 |
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Zusammenfassung: | 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. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/s41586-020-03047-0 |