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:

Electrical synapses coordinate activity in the suprachiasmatic nucleus

Nature Neuroscience volume 8, pages 61–66 (2005)Cite this article

Abstract

In the suprachiasmatic nucleus (SCN), the master circadian pacemaker, neurons show circadian variations in firing frequency. There is also considerable synchrony of spiking across SCN neurons on a scale of milliseconds, but the mechanisms are poorly understood. Using paired whole-cell recordings, we have found that many neurons in the rat SCN communicate via electrical synapses. Spontaneous spiking was often synchronized in pairs of electrically coupled neurons, and the degree of this synchrony could be predicted from the magnitude of coupling. In wild-type mice, as in rats, the SCN contained electrical synapses, but electrical synapses were absent in connexin36-knockout mice. The knockout mice also showed dampened circadian activity rhythms and a delayed onset of activity during transition to constant darkness. We suggest that electrical synapses in the SCN help to synchronize its spiking activity, and that such synchrony is necessary for normal circadian behavior.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Electrical coupling in the SCN.
Figure 2: Electrical synapses synchronize spiking between SCN pairs.
Figure 3: Electrophysiology and circadian behavior in wild-type (WT) and Cx36-knockout (KO) mice.
Figure 4: Means of circadian measures of locomotor activity across blocks of 10 d for the four wild-type (WT) and four Cx36-knockout (KO) mice that were maintained in constant darkness (DD) for the full 50 d.

Similar content being viewed by others

References

  1. Moore, R.Y. & Eichler, V.B. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 42, 201–206 (1972).

    Article  CAS  Google Scholar 

  2. Stephan, F.K. & Zucker, I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc. Natl. Acad. Sci. USA 69, 1583–1586 (1972).

    Article  CAS  Google Scholar 

  3. Lehman, M.N. et al. Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. J. Neurosci. 7, 1626–1638 (1987).

    Article  CAS  Google Scholar 

  4. Ralph, M.R., Foster, R.G., Davis, F.C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).

    Article  CAS  Google Scholar 

  5. Berson, D.M., Dunn, F.A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002).

    Article  CAS  Google Scholar 

  6. Aston-Jones, G., Chen, S., Zhu, Y. & Oshinsky, M.L. A neural circuit for circadian regulation of arousal. Nat. Neurosci. 4, 732–738 (2001).

    Article  CAS  Google Scholar 

  7. Teclemariam-Mesbah, R., Ter Horst, G.J., Postema, F., Wortel, J. & Buijs, R.M. Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway. J. Comp. Neurol. 406, 171–182 (1999).

    Article  CAS  Google Scholar 

  8. Brandstaetter, R. Circadian lessons from peripheral clocks: is the time of the mammalian pacemaker up? Proc. Natl. Acad. Sci. USA 101, 5699–5700 (2004).

    Article  CAS  Google Scholar 

  9. LeSauter, J. & Silver, R. Output signals of the SCN. Chronobiol. Int. 15, 535–550 (1998).

    Article  CAS  Google Scholar 

  10. Schwartz, W.J. & Gainer, H. Suprachiasmatic nucleus: use of 14C-labeled deoxyglucose uptake as a functional marker. Science 197, 1089–1091 (1977).

    Article  CAS  Google Scholar 

  11. Inouye, S.T. & Kawamura, H. Persistence of circadian rhythmicity in a mammalian hypothalamic “island” containing the suprachiasmatic nucleus. Proc. Natl. Acad. Sci. USA 76, 5962–5966 (1979).

    Article  CAS  Google Scholar 

  12. Shibata, S., Oomura, Y., Kita, H. & Hattori, K. Circadian rhythmic changes of neuronal activity in the suprachiasmatic nucleus of the rat hypothalamic slice. Brain Res. 247, 154–158 (1982).

    Article  CAS  Google Scholar 

  13. Groos, G. & Hendriks, J. Circadian rhythms in electrical discharge of rat suprachiasmatic neurones recorded in vitro. Neurosci. Lett. 34, 283–288 (1982).

    Article  CAS  Google Scholar 

  14. Prosser, R.A. & Gillette, M.U. The mammalian circadian clock in the suprachiasmatic nuclei is reset in vitro by cAMP. J. Neurosci. 9, 1073–1081 (1989).

    Article  CAS  Google Scholar 

  15. Welsh, D.K., Logothetis, D.E., Meister, M. & Reppert, S.M. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14, 697–706 (1995).

    Article  CAS  Google Scholar 

  16. van den Pol, A.N. Gamma-aminobutyrate, gastrin releasing peptide, serotonin, somatostatin, and vasopressin: ultrastructural immunocytochemical localization in presynaptic axons in the suprachiasmatic nucleus. Neuroscience 17, 643–659 (1986).

    Article  CAS  Google Scholar 

  17. Strecker, G.J., Wuarin, J.P. & Dudek, F.E. GABAA-mediated local synaptic pathways connect neurons in the rat suprachiasmatic nucleus. J. Neurophysiol. 78, 2217–2220 (1997).

    Article  CAS  Google Scholar 

  18. Wagner, S., Castel, M., Gainer, H. & Yarom, Y. GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature 387, 598–603 (1997).

    Article  CAS  Google Scholar 

  19. Abrahamson, E.E. & Moore, R.Y. Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res. 916, 172–191 (2001).

    Article  CAS  Google Scholar 

  20. Bouskila, Y. & Dudek, F.E. Neuronal synchronization without calcium-dependent synaptic transmission in the hypothalamus. Proc. Natl. Acad. Sci. USA 90, 3207–3210 (1993).

    Article  CAS  Google Scholar 

  21. Schwartz, W.J., Gross, R.A. & Morton, M.T. The suprachiasmatic nuclei contain a tetrodotoxin-resistant circadian pacemaker. Proc. Natl. Acad. Sci. USA 84, 1694–1698 (1987).

    Article  CAS  Google Scholar 

  22. Shibata, S. & Moore, R.Y. Tetrodotoxin does not affect circadian rhythms in neuronal activity and metabolism in rodent suprachiasmatic nucleus in vitro. Brain Res. 606, 259–266 (1993).

    Article  CAS  Google Scholar 

  23. Yamaguchi, S. et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302, 1408–1412 (2003).

    Article  CAS  Google Scholar 

  24. Connors, B.W. & Long, M.A. Electrical synapses in the mammalian brain. Annu. Rev. Neurosci. 27, 393–418 (2004).

    Article  CAS  Google Scholar 

  25. Jiang, Z.G., Yang, Y.Q. & Allen, C.N. Tracer and electrical coupling of rat suprachiasmatic nucleus neurons. Neuroscience 77, 1059–1066 (1997).

    Article  CAS  Google Scholar 

  26. Colwell, C.S. Rhythmic coupling among cells in the suprachiasmatic nucleus. J. Neurobiol. 43, 379–388 (2000).

    Article  CAS  Google Scholar 

  27. Gibson, J.R., Beierlein, M. & Connors, B.W. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79 (1999).

    Article  CAS  Google Scholar 

  28. Landisman, C.E. et al. Electrical synapses in the thalamic reticular nucleus. J. Neurosci. 22, 1002–1009 (2002).

    Article  CAS  Google Scholar 

  29. Long, M.A., Deans, M.R., Paul, D.L. & Connors, B.W. Rhythmicity without synchrony in the electrically uncoupled inferior olive. J. Neurosci. 22, 10898–10905 (2002).

    Article  CAS  Google Scholar 

  30. Schaap, J. et al. Neurons of the rat suprachiasmatic nucleus show a circadian rhythm in membrane properties that is lost during prolonged whole-cell recording. Brain Res. 815, 154–166 (1999).

    Article  CAS  Google Scholar 

  31. Deans, M.R., Gibson, J.R., Sellitto, C., Connors, B.W. & Paul, D.L. Synchronous activity of inhibitory networks in neocortex requires electrical synapses containing connexin36. Neuron 31, 477–485 (2001).

    Article  CAS  Google Scholar 

  32. Amitai, Y. et al. The spatial dimensions of electrically coupled networks of interneurons in the neocortex. J. Neurosci. 22, 4142–4152 (2002).

    Article  CAS  Google Scholar 

  33. Long, M.A., Landisman, C.E. & Connors, B.W. Small clusters of electrically coupled neurons generate synchronous rhythms in the thalamic reticular nucleus. J. Neurosci. 24, 341–349 (2004).

    Article  CAS  Google Scholar 

  34. Blatow, M. et al. A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38, 805–817 (2003).

    Article  CAS  Google Scholar 

  35. Chu, Z., Galarreta, M. & Hestrin, S. Synaptic interactions of late-spiking neocortical neurons in layer 1. J. Neurosci. 23, 96–102 (2003).

    Article  CAS  Google Scholar 

  36. Pennartz, C.M., De Jeu, M.T., Geurtsen, A.M., Sluiter, A.A. & Hermes, M.L. Electrophysiological and morphological heterogeneity of neurons in slices of rat suprachiasmatic nucleus. J. Physiol. (Lond.) 506, 775–793 (1998).

    Article  CAS  Google Scholar 

  37. Shinohara, K., Funabashi, T., Nakamura, T.J. & Kimura, F. Effects of estrogen and progesterone on the expression of connexin-36 mRNA in the suprachiasmatic nucleus of female rats. Neurosci. Lett. 309, 37–40 (2001).

    Article  CAS  Google Scholar 

  38. Pennartz, C.M., de Jeu, M.T., Bos, N.P., Schaap, J. & Geurtsen, A.M. Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 416, 286–290 (2002).

    Article  CAS  Google Scholar 

  39. Christie, M.J., Williams, J.T. & North, R.A. Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats. J. Neurosci. 9, 3584–3589 (1989).

    Article  CAS  Google Scholar 

  40. Grace, A.A. & Bunney, B.S. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons–3. Evidence for electrotonic coupling. Neuroscience 10, 333–348 (1983).

    Article  CAS  Google Scholar 

  41. Perez-Armendariz, M., Roy, C., Spray, D.C. & Bennett, M.V. Biophysical properties of gap junctions between freshly dispersed pairs of mouse pancreatic beta cells. Biophys. J. 59, 76–92 (1991).

    Article  CAS  Google Scholar 

  42. Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001).

    Article  CAS  Google Scholar 

  43. Cheng, M.Y. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002).

    Article  CAS  Google Scholar 

  44. Harris, A.L. Emerging issues of connexin channels: biophysics fills the gap. Q. Rev. Biophys. 34, 325–472 (2001).

    Article  CAS  Google Scholar 

  45. Srinivas, M. et al. Functional properties of channels formed by the neuronal gap junction protein connexin36. J. Neurosci. 19, 9848–9855 (1999).

    Article  CAS  Google Scholar 

  46. Kistler, W.M. et al. Analysis of Cx36 knockout does not support tenet that olivary gap junctions are required for complex spike synchronization and normal motor performance. Ann. NY Acad. Sci. 978, 391–404 (2002).

    Article  CAS  Google Scholar 

  47. Guldenagel, M. et al. Visual transmission deficits in mice with targeted disruption of the gap junction gene connexin36. J. Neurosci. 21, 6036–6044 (2001).

    Article  CAS  Google Scholar 

  48. Deans, M.R., Volgyi, B., Goodenough, D.A., Bloomfield, S.A. & Paul, D.L. Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina. Neuron 36, 703–712 (2002).

    Article  CAS  Google Scholar 

  49. Lupi, D. et al. Transgenic ablation of rod photoreceptors alters the circadian phenotype of mice. Neuroscience 89, 363–374 (1999).

    Article  CAS  Google Scholar 

  50. Sokolove, P.G. & Bushell, W.N. The chi square periodogram: its utility for analysis of circadian rhythms. J. Theor. Biol. 72, 131–160 (1978).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Patrick for technical help, A. Jackson, M. Carskadon and D. Berson for comments on the manuscript, and M. Deans and D. Paul for the Cx36-knockout mouse line. This research was supported by a Sidney A. Fox and Dorothea Doctors Fox Postdoctoral Fellowship to M.A.L. and by US National Institutes of Health grants MH60284 to R.D.B. and NS25983 and DA12500 to B.W.C.

Author information

Author notes

  1. Michael A Long

    Present address: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, E19-528 77 Massachusetts Ave., Cambridge, Massachusetts, 02139, USA

  2. Michael A Long and Michael J Jutras: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Brown University, Providence, 02912, Rhode Island, USA

    Michael A Long, Michael J Jutras, Barry W Connors & Rebecca D Burwell

  2. Department of Psychology, Brown University, Providence, 02912, Rhode Island, USA

    Michael J Jutras & Rebecca D Burwell

Authors
  1. Michael A Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J Jutras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barry W Connors
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rebecca D Burwell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barry W Connors.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Long, M., Jutras, M., Connors, B. et al. Electrical synapses coordinate activity in the suprachiasmatic nucleus. Nat Neurosci 8, 61–66 (2005). https://doi.org/10.1038/nn1361

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1361

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