Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype

Abstract

Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1–deficient (Kcnk2−/−) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: 'Antidepressant-like' behavior in Kcnk2−/− mice.
Figure 2: TREK-1 channel and stress.
Figure 3: Effect of antidepressants in Kcnk2−/− and Kcnk4−/− mice.
Figure 4: Increased fluoxetine-induced neurogenesis in hippocampus of TREK-1–deficient mice.
Figure 5: The TREK-1 channel and the 5-HT system.

Similar content being viewed by others

References

  1. Lapin, I. & Oxenkrug, G. Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1, 132–136 (1969).

    Article  CAS  Google Scholar 

  2. Coppen, A. The biochemistry of affective disorders. Br. J. Psychiatry 113, 1237–1264 (1967).

    Article  CAS  Google Scholar 

  3. Delgado, P. et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol. Psychiatry 46, 212–220 (1999).

    Article  CAS  Google Scholar 

  4. Nestler, E.J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002).

    Article  CAS  Google Scholar 

  5. Maes, M. & Meltzer, H. The serotonin hypothesis of major depression. in Psychopharmacology The Fourth Generation of Progress (eds. Bloom, F.E. & Kupfer, D.J.) 933–944 (Raven, New York, 1995).

    Google Scholar 

  6. Owens, M. Molecular and cellular mechanisms of antidepressant drugs. Depress. Anxiety 4, 153–159 (1996).

    Article  Google Scholar 

  7. Haddjeri, N., Blier, P. & de Montigny, C. Long-term antidepressant treatments result in a tonic activation of forebrain 5–HT1A receptors. J. Neurosci. 18, 10150–10156 (1998).

    Article  CAS  Google Scholar 

  8. Mayorga, A. et al. Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J. Pharmacol. Exp. Ther. 298, 1101–1107 (2001).

    CAS  Google Scholar 

  9. Fink, M. et al. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J. 15, 6854–6862 (1996).

    Article  CAS  Google Scholar 

  10. Lesage, F. & Lazdunski, M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. Renal Physiol. 279, F793–F801 (2000).

    Article  CAS  Google Scholar 

  11. Patel, A.J. & Honore, E. Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci. 24, 339–346 (2001).

    Article  CAS  Google Scholar 

  12. Patel, A.J. et al. A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J. 17, 4283–4290 (1998).

    Article  CAS  Google Scholar 

  13. Chemin, J. et al. Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO J. 22, 5403–5411 (2003).

    Article  CAS  Google Scholar 

  14. Siegelbaum, S.A., Camardo, J.S. & Kandel, E.R. Serotonin and cyclic AMP close single K+ channels in Aplysia sensory neurones. Nature 299, 413–417 (1982).

    Article  CAS  Google Scholar 

  15. Kandel, E.R. & Schwartz, J.H. Molecular biology of learning: modulation of transmitter release. Science 218, 433–443 (1982).

    Article  CAS  Google Scholar 

  16. Talley, E.M., Solorzano, G., Lei, Q., Kim, D. & Bayliss, D.A. CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J. Neurosci. 21, 7491–7505 (2001).

    Article  CAS  Google Scholar 

  17. Maingret, F. et al. TREK-1 is a heat-activated background K(+) channel. EMBO J. 19, 2483–2491 (2000).

    Article  CAS  Google Scholar 

  18. Heurteaux, C. et al. TREK-1, a K(+) channel involved in neuroprotection and general anesthesia. EMBO J. 23, 2684–2695 (2004).

    Article  CAS  Google Scholar 

  19. Porsolt, R.D., Le Pichon, M. & Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730–732 (1977).

    Article  CAS  Google Scholar 

  20. Nestler, E.J. et al. Preclinical models: status of basic research in depression. Biol. Psychiatry 52, 503–528 (2002).

    Article  Google Scholar 

  21. Cryan, J.F., Page, M.E. & Lucki, I. Noradrenergic lesions differentially alter the antidepressant-like effects of reboxetine in a modified forced swim test. Eur. J. Pharmacol. 436, 197–205 (2002).

    Article  CAS  Google Scholar 

  22. Steru, L., Chermat, R., Thierry, B. & Simon, P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl.) 85, 367–370 (1985).

    Article  CAS  Google Scholar 

  23. Ripoll, N., David, D., Dailly, E., Hascoet, M. & Bourin, M. Antidepressant-like effects in various mice strains in the tail suspension. Behav. Brain Res. 143, 193–200 (2003).

    Article  CAS  Google Scholar 

  24. Cryan, J. & Holmes, A. The ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4, 775–790 (2005).

    Article  CAS  Google Scholar 

  25. Kameyama, T., Nagasaka, M. & Yamada, K. Effects of antidepressant drugs on a quickly-learned conditioned-suppression response in mice. Neuropharmacology 24, 285–290 (1985).

    Article  CAS  Google Scholar 

  26. Maier, S. Learned helplessness and animal models of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 8, 435–446 (1984).

    Article  CAS  Google Scholar 

  27. Caldarone, B., George, T., Zachariou, V. & Picciotto, M. Gender differences in learned helplessness behavior are influenced by genetic background. Pharmacol. Biochem. Behav. 66, 811–817 (2000).

    Article  CAS  Google Scholar 

  28. Caldarone, B. et al. Sex differences in response to oral amitriptyline in three animal models. Psychopharmacology (Berl.) 170, 94–101 (2003).

    Article  CAS  Google Scholar 

  29. Fink, M. et al. A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J. 17, 3297–3308 (1998).

    Article  CAS  Google Scholar 

  30. Reyes, R. et al. Immunolocalization of the arachidonic acid and mechanosensitive baseline TRAAK potassium channel in the nervous system. Neuroscience 95, 893–901 (2000).

    Article  CAS  Google Scholar 

  31. Maingret, F., Fosset, M., Lesage, F., Lazdunski, M. & Honore, E. TRAAK is a mammalian neuronal mechano-gated K+ channel. J. Biol. Chem. 274, 1381–1387 (1999).

    Article  CAS  Google Scholar 

  32. Sheline, Y.I., Wang, P.W., Gado, M.H., Csernansky, J.G. & Vannier, M.W. Hippocampal atrophy in recurrent major depression. Proc. Natl. Acad. Sci. USA 93, 3908–3913 (1996).

    Article  CAS  Google Scholar 

  33. Heuser, I.J. et al. Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects. Am. J. Psychiatry 153, 93–99 (1996).

    Article  CAS  Google Scholar 

  34. Hermann, G. et al. Stress-induced changes attributable to the sympathetic nervous system. J. Neuroimmunol. 53, 173–180 (1994).

    Article  CAS  Google Scholar 

  35. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

  36. Malberg, J. Implications of adult hippocampal neurogenesis in antidepressant action. J. Psychiatry Neurosci. 29, 196–205 (2004).

    PubMed  PubMed Central  Google Scholar 

  37. Couillard-Despres, S. et al. Doublecortin expression levels in adult brain reflect neurogenesis. Eur. J. Neurosci. 21, 1–14 (2005).

    Article  Google Scholar 

  38. Kennard, L.E. et al. Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br. J. Pharmacol. 144, 821–829 (2005).

    Article  CAS  Google Scholar 

  39. Karson, C.N. et al. Human brain fluoxetine concentrations. J. Neuropsychiatry Clin. Neurosci. 5, 322–329 (1993).

    Article  CAS  Google Scholar 

  40. Komoroski, R.A. et al. In vivo 19F spin relaxation and localized spectroscopy of fluoxetine in human brain. Magn. Reson. Med. 31, 204–211 (1994).

    Article  CAS  Google Scholar 

  41. Bolo, N.R. et al. Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy. Neuropsychopharmacology 23, 428–438 (2000).

    Article  CAS  Google Scholar 

  42. Redrobe, J., Dumont, Y., Fournier, A., Baker, G. & Quirion, R. Role of serotonin (5-HT) in the antidepressant-like properties of neuropeptide Y (NPY) in the mouse forced swim test. Peptides 26, 1394–1400 (2005).

    Article  CAS  Google Scholar 

  43. Blier, P. & de Montigny, C. Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology 21, 91S–98S (1999).

    Article  CAS  Google Scholar 

  44. Descarries, L., Watkins, K., Garcia, S. & Beaudet, A. The serotonin neurons in nucleus raphe dorsalis of adult rat: a light and electron microscope radioautographic study. J. Comp. Neurol. 207, 239–254 (1982).

    Article  CAS  Google Scholar 

  45. Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002).

    Article  CAS  Google Scholar 

  46. Xu, X., Pan, Y. & Wang, X. mRNA expression of the lipid and mechano-gated 2P domain K+ channels. J. Neurogenet. 16, 263–269 (2002).

    Article  CAS  Google Scholar 

  47. Caccia, S., Cappi, M., Fracasso, C. & Garattini, S. Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat. Psychopharmacology (Berl.) 100, 509–514 (1990).

    Article  CAS  Google Scholar 

  48. Gingrich, J.A. & Hen, R. Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology (Berl.) 155, 1–10 (2001).

    Article  CAS  Google Scholar 

  49. Gobbi, G., Murphy, D.L., Lesch, K. & Blier, P. Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J. Pharmacol. Exp. Ther. 296, 987–995 (2001).

    CAS  PubMed  Google Scholar 

  50. Kandel, E.R. & Spencer, W.A. Electrophysiology of hippocampal neurons. II. After-potentials and repetitive firing. J. Neurophysiol. 24, 243–259 (1961).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the CNRS and the Institut Paul Hamel. G.L. received a Canadian Institute for Health Research/Wyeth Fellowship, X.-D.P. received a Québec Merit Fellowship, G.D. was a National Researcher of the Fonds de la Recherche en Santé du Québec and S.T. received a Deutsche Forschungsgemeinschaft Fellowship. We are very grateful to Y. Jacomet for the MRS analysis of brain fluoxetine concentrations, to F. Lesage (CNRS Unité Mixte de Recherche, UMR 6097) for the TREK-1 antibody and to J. Costentin for discussions, to C. Gandin and M. Jodar for their technical help and to Y. Benhamou and L. Martin for secretarial assistance.

Author information

Authors and Affiliations

Authors

Contributions

C.H. behavioral experiments, localization studies, data analysis and writing. G.L. in vivo electrophysiology and data analysis. N.G. production of knockout mice. M.E.Y. behavioral experiments. S.T. in vitro electrophysiology of antidepressants. X.-D.P. in vivo electrophysiology. F.N. behavioral experiments. N.B. localization studies and data analysis. C.W. localization studies and statistics. M.B. localization studies and biochemical experiments. G.G. in vivo electrophysiology. J.-M.V. behavioral studies. G.D. in vivo electrophysiological experiments, data analysis and writing. M.L. overall organization of the research work between the different authors and different teams, and writing.

Note: Supplementary information is available on the Nature Neuroscience website.

Corresponding author

Correspondence to Michel Lazdunski.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

TREK-1 immunolocalization throughout the network of limbic, striatal and prefrontal cortical neuronal circuits. (PDF 1149 kb)

Supplementary Fig. 2

TRAAK expression in 5-HT neurons of the dorsal raphe nucleus. (PDF 1975 kb)

Supplementary Fig. 3

5-HT selective reuptake inhibitors (SSRIs) inhibit human TREK-1 but not TRAAK currents. (PDF 280 kb)

Supplementary Fig. 4

Mean whole-brain fluoxetine concentrations after acute and chronic fluoxetine treatment. (PDF 28 kb)

Supplementary Note (PDF 157 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heurteaux, C., Lucas, G., Guy, N. et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9, 1134–1141 (2006). https://doi.org/10.1038/nn1749

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1749

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing