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NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

Abstract

Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear1,2,3. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks1,2,3, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients3. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

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Figure 1: Time course of NMDAR antagonist-mediated antidepressant-like behavioural effects.
Figure 2: BDNF translation in the antidepressant effects of NMDAR antagonists.
Figure 3: Ketamine blocks NMDAR spontaneous activity, reduces the level of eEF2 phosphorylation and strengthens synaptic responses.
Figure 4: Rapid antidepressant-like behaviour is mediated by decreased p-eEF2 and increased BDNF translation.

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Acknowledgements

We thank M. A. Mahgoub for assistance with the animal experiments, S. Birnbaum and A. Pettersen for assistance with the behavioural testing and members of the Monteggia and Kavalali laboratories for discussions and comments on the manuscript. This work was supported by grant MH070727 (L.M.M.), grant MH066198 (E.T.K.) and the Division of Basic Sciences Training Program at UT Southwestern Medical Center, T32 MH 76690-02 (A.E.A.). E.T.K. is an Established Investigator of the American Heart Association.

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Authors

Contributions

A.E.A. performed the behavioural experiments. A.E.A., M.A. and M.F.L. contributed to the molecular experiments. E.N. performed the electrophysiology experiments, E.S.N. performed the TrkB behavioural experiments and A.E.A. and P.-f.C. performed the statistical analyses. A.E.A. also made the figures and wrote the corresponding sections of the paper. E.T.K. and L.M.M. designed the study, supervised the experiments and wrote the paper.

Corresponding authors

Correspondence to Ege T. Kavalali or Lisa M. Monteggia.

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The authors declare no competing financial interests.

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Autry, A., Adachi, M., Nosyreva, E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011). https://doi.org/10.1038/nature10130

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