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:

T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites

Nature Neuroscience volume 11, pages 683–692 (2008)Cite this article

Abstract

T-type Ca2+ channels (T channels) underlie rhythmic burst discharges during neuronal oscillations that are typical during sleep. However, the Ca2+-dependent effectors that are selectively regulated by T currents remain unknown. We found that, in dendrites of nucleus reticularis thalami (nRt), intracellular Ca2+ concentration increases were dominated by Ca2+ influx through T channels and shaped rhythmic bursting via competition between Ca2+-dependent small-conductance (SK)-type K+ channels and Ca2+ uptake pumps. Oscillatory bursting was initiated via selective activation of dendritically located SK2 channels, whereas Ca2+ sequestration by sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) and cumulative T channel inactivation dampened oscillations. Sk2−/− (also known as Kcnn2) mice lacked cellular oscillations, showed a greater than threefold reduction in low-frequency rhythms in the electroencephalogram of non–rapid-eye-movement sleep and had disrupted sleep. Thus, the interplay of T channels, SK2 channels and SERCAs in nRt dendrites comprises a specialized Ca2+ signaling triad to regulate oscillatory dynamics related to sleep.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: SK currents are selectively activated by T currents to control nRt cell oscillations.
Figure 2: T channels dominate dendritic [Ca2+]i increases during low-threshold bursts.
Figure 3: SK currents in nRt are carried by SK2-containing SK channels.
Figure 4: SK2 channel subunits are selectively expressed in nRt dendrites.
Figure 5: Repetitive low-threshold bursting is accompanied by a decrease in the amplitude of Δ[Ca2+]i.
Figure 6: SERCAs antagonize SK2 current activation by T-type Ca2+, but not by HVA Ca2+, currents.
Figure 7: SERCAs modulate the strength of nRt oscillations.
Figure 8: Lack of Sk2 greatly impacts the EEG and fragmentation of NREMS.

Similar content being viewed by others

References

  1. Steriade, M. Grouping of brain rhythms in corticothalamic systems. Neuroscience 137, 1087–1106 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Crunelli, V., Cope, D.W. & Hughes, S.W. Thalamic T-type Ca2+ channels and NREM sleep. Cell Calcium 40, 175–190 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Contreras, D. The role of T-channels in the generation of thalamocortical rhythms. CNS Neurol. Disord. Drug Targets 5, 571–585 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Perez-Reyes, E. Molecular physiology of low voltage–activated T-type calcium channels. Physiol. Rev. 83, 117–161 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Pinault, D. The thalamic reticular nucleus: structure, function and concept. Brain Res. Brain Res. Rev. 46, 1–31 (2004).

    Article  PubMed  Google Scholar 

  6. Fuentealba, P. & Steriade, M. The reticular nucleus revisited: intrinsic and network properties of a thalamic pacemaker. Prog. Neurobiol. 75, 125–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Domich, L., Oakson, G. & Steriade, M. Thalamic burst patterns in the naturally sleeping cat: a comparison between cortically projecting and reticularis neurones. J. Physiol. (Lond.) 379, 429–449 (1986).

    Article  CAS  Google Scholar 

  8. Talley, E.M. et al. Differential distribution of three members of a gene family encoding low voltage–activated (T-type) calcium channels. J. Neurosci. 19, 1895–1911 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Joksovic, P.M., Bayliss, D.A. & Todorovic, S.M. Different kinetic properties of two T-type Ca2+ currents of rat reticular thalamic neurones and their modulation by enflurane. J. Physiol. (Lond.) 566, 125–142 (2005).

    Article  CAS  Google Scholar 

  10. Avanzini, G., de Curtis, M., Panzica, F. & Spreafico, R. Intrinsic properties of nucleus reticularis thalami neurones of the rat studied in vitro. J. Physiol. (Lond.) 416, 111–122 (1989).

    Article  CAS  Google Scholar 

  11. Bal, T. & McCormick, D.A. Mechanisms of oscillatory activity in guinea-pig nucleus reticularis thalami in vitro: a mammalian pacemaker. J. Physiol. (Lond.) 468, 669–691 (1993).

    Article  CAS  Google Scholar 

  12. Blethyn, K.L., Hughes, S.W., Toth, T.I., Cope, D.W. & Crunelli, V. Neuronal basis of the slow (<1 Hz) oscillation in neurons of the nucleus reticularis thalami in vitro. J. Neurosci. 26, 2474–2486 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Huguenard, J.R. & McCormick, D.A. Thalamic synchrony and dynamic regulation of global forebrain oscillations. Trends Neurosci. 30, 350–356 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Pedarzani, P. et al. Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J. Biol. Chem. 276, 9762–9769 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Ogden, D., Khodakhah, K., Carter, T., Thomas, M. & Capiod, T. Analogue computation of transient changes of intracellular free Ca2+ concentration with the low affinity Ca2+ indicator furaptra during whole-cell patch-clamp recording. Pflugers Arch. 429, 587–591 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Destexhe, A., Contreras, D., Steriade, M., Sejnowski, T.J. & Huguenard, J.R. In vivo, in vitro and computational analysis of dendritic calcium currents in thalamic reticular neurons. J. Neurosci. 16, 169–185 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Debarbieux, F., Brunton, J. & Charpak, S. Effect of bicuculline on thalamic activity: a direct blockade of IAHP in reticularis neurons. J. Neurophysiol. 79, 2911–2918 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Canepari, M., Auger, C. & Ogden, D. Ca2+ ion permeability and single-channel properties of the metabotropic slow EPSC of rat Purkinje neurons. J. Neurosci. 24, 3563–3573 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Stocker, M. & Pedarzani, P. Differential distribution of three Ca2+-activated K+ channel subunits, SK1, SK2 and SK3, in the adult rat central nervous system. Mol. Cell. Neurosci. 15, 476–493 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Bond, C.T. et al. Small conductance Ca2+-activated K+ channel knockout mice reveal the identity of calcium-dependent afterhyperpolarization currents. J. Neurosci. 24, 5301–5306 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Stocker, M. Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat. Rev. Neurosci. 5, 758–770 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Bond, C.T., Maylie, J. & Adelman, J.P. SK channels in excitability, pacemaking and synaptic integration. Curr. Opin. Neurobiol. 15, 305–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Cui, G., Okamoto, T. & Morikawa, H. Spontaneous opening of T-type Ca2+ channels contributes to the irregular firing of dopamine neurons in neonatal rats. J. Neurosci. 24, 11079–11087 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Richter, T.A., Kolaj, M. & Renaud, L.P. Low voltage–activated Ca2+ channels are coupled to Ca2+-induced Ca2+ release in rat thalamic midline neurons. J. Neurosci. 25, 8267–8271 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Bildl, W. et al. Protein kinase CK2 is coassembled with small conductance Ca2+-activated K+ channels and regulates channel gating. Neuron 43, 847–858 (2004).

    Article  CAS  Google Scholar 

  26. Buzsáki, G. Theta oscillations in the hippocampus. Neuron 33, 325–340 (2002).

    Article  PubMed  Google Scholar 

  27. Kramár, E.A. et al. A novel mechanism for the facilitation of theta-induced long-term potentiation by brain-derived neurotrophic factor. J. Neurosci. 24, 5151–5161 (2004).

    Article  PubMed  Google Scholar 

  28. Franken, P., Malafosse, A. & Tafti, M. Genetic variation in EEG activity during sleep in inbred mice. Am. J. Physiol. 275, R1127–R1137 (1998).

    CAS  PubMed  Google Scholar 

  29. Gottesmann, C. The transition from slow-wave sleep to paradoxical sleep: evolving facts and concepts of the neurophysiological processes underlying the intermediate stage of sleep. Neurosci. Biobehav. Rev. 20, 367–387 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Franken, P., Malafosse, A. & Tafti, M. Genetic determinants of sleep regulation in inbred mice. Sleep 22, 155–169 (1999).

    CAS  PubMed  Google Scholar 

  31. Diana, M.A. et al. T-type and L-type Ca2+ conductances define and encode the bimodal firing pattern of vestibulocerebellar unipolar brush cells. J. Neurosci. 27, 3823–3838 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Egger, V., Svoboda, K. & Mainen, Z.F. Mechanisms of lateral inhibition in the olfactory bulb: efficiency and modulation of spike-evoked calcium influx into granule cells. J. Neurosci. 23, 7551–7558 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Ivanov, A.I. & Calabrese, R.L. Intracellular Ca2+ dynamics during spontaneous and evoked activity of leech heart interneurons: low-threshold Ca currents and graded synaptic transmission. J. Neurosci. 20, 4930–4943 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Munsch, T., Budde, T. & Pape, H.C. Voltage-activated intracellular calcium transients in thalamic relay cells and interneurons. Neuroreport 8, 2411–2418 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Kuisle, M. et al. Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy. J. Physiol. (Lond.) 575, 83–100 (2006).

    Article  CAS  Google Scholar 

  36. Frazier, C.J. et al. Gating kinetics of the α1I T-type calcium channel. J. Gen. Physiol. 118, 457–470 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Uebachs, M., Schaub, C., Perez-Reyes, E. & Beck, H. T-type Ca2+ channels encode prior neuronal activity as modulated recovery rates. J. Physiol. (Lond.) 571, 519–536 (2006).

    Article  CAS  Google Scholar 

  38. Ngo-Anh, T.J. et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat. Neurosci. 8, 642–649 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Marrion, N.V. & Tavalin, S.J. Selective activation of Ca2+-activated K+ channels by colocalized Ca2+ channels in hippocampal neurons. Nature 395, 900–905 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Kohler, M. et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273, 1709–1714 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Cai, X. et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44, 351–364 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Pape, H.C., Munsch, T. & Budde, T. Novel vistas of calcium-mediated signaling in the thalamus. Pflugers Arch. 448, 131–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Misquitta, C.M., Mack, D.P. & Grover, A.K. Sarco/endoplasmic reticulum Ca2+ (SERCA)-pumps: link to heart beats and calcium waves. Cell Calcium 25, 277–290 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Lytton, J., Westlin, M., Burk, S.E., Shull, G.E. & MacLennan, D.H. Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps. J. Biol. Chem. 267, 14483–14489 (1992).

    CAS  PubMed  Google Scholar 

  45. Fierro, L., DiPolo, R. & Llanò, I. Intracellular calcium clearance in Purkinje cell somata from rat cerebellar slices. J. Physiol. (Lond.) 510, 499–512 (1998).

    Article  CAS  Google Scholar 

  46. Amzica, F., Nunez, A. & Steriade, M. Delta frequency (1–4 Hz) oscillations of perigeniculate thalamic neurons and their modulation by light. Neuroscience 51, 285–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. Vyazovskiy, V.V. et al. Sleep EEG in mice that are deficient in the potassium channel subunit K.v.3.2. Brain Res. 947, 204–211 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Joho, R.H., Marks, G.A. & Espinosa, F. Kv3 potassium channels control the duration of different arousal states by distinct stochastic and clock-like mechanisms. Eur. J. Neurosci. 23, 1567–1574 (2006).

    Article  PubMed  Google Scholar 

  49. Liguori, R. et al. Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124, 2417–2426 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Luján, R., Nusser, Z., Roberts, J.D., Shigemoto, R. & Somogyi, P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Tafti, K. Vogt and N. Wanaverbecq for constructive input and A. Reisch for carrying out preliminary electrophysiological experiments. We thank L. Acsády, A. Destexhe, B. Gähwiler, U. Gerber, C. Kopp and D. Ulrich for stimulating discussions and helpful comments on the manuscript. This work was supported by grants from the Swiss National Science Foundation (A.L.), the US National Institutes of Health (P.F. and J.P.A.) and the Spanish Ministry of Education and Science (R.L.).

Author information

Authors and Affiliations

  1. Division of Pharmacology and Neurobiology, Biozentrum, University of Basel, Klingelbergstr. 70, Basel, CH-4056, Switzerland

    Lucius Cueni, Marco Canepari & Anita Lüthi

  2. Departamento de Ciencias Médicas, Crib-Facultad De Medicina, Campus Biosanitario C/ Almansa 14, Universidad de Castilla-La Mancha, Albacete, 02006, Spain

    Rafael Luján

  3. Center for Integrative Genomics, Génopode Building, Quartier UNIL-Sorge, University of Lausanne, Lausanne-Dorigny, CH-1015, Switzerland

    Yann Emmenegger & Paul Franken

  4. Department of Anatomy, Hokkaido University School of Medicine, Kita-15 Nishi-7 Kita-ku, Sapporo, 060-8638, Japan

    Masahiko Watanabe

  5. Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, 97239, Oregon, USA

    Chris T Bond & John P Adelman

  6. Department of Cell Biology and Morphology, Faculty of Biology and Medicine, Rue du Bugnon 9, University of Lausanne, Lausanne, CH-1005, Switzerland

    Anita Lüthi

Authors
  1. Lucius Cueni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Canepari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rafael Luján
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yann Emmenegger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masahiko Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chris T Bond
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Paul Franken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John P Adelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anita Lüthi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anita Lüthi.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Table 1, Supplementary Note and Supplementary Methods (PDF 2441 kb)

Supplementary Movie 1

Fluorescent signals in a dendrite of a nRt neuron filled with the Ca2+ dye magfura-2 during a dampened electrical oscillation. (WMV 482 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cueni, L., Canepari, M., Luján, R. et al. T-type Ca2+ channels, SK2 channels and SERCAs gate sleep-related oscillations in thalamic dendrites. Nat Neurosci 11, 683–692 (2008). https://doi.org/10.1038/nn.2124

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2124

This article is cited by

Search

Advanced 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