Abstract
Spontaneous action potentials in the suprachiasmatic nucleus (SCN) are necessary for normal circadian timing of behavior in mammals. The SCN exhibits a daily oscillation in spontaneous firing rate (SFR), but the ionic conductances controlling SFR and the relationship of SFR to subsequent circadian behavioral rhythms are not understood. We show that daily expression of the large conductance Ca2+-activated K+ channel (BK) in the SCN is controlled by the intrinsic circadian clock. BK channel–null mice (Kcnma1−/−) have increased SFRs in SCN neurons selectively at night and weak circadian amplitudes in multiple behaviors timed by the SCN. Kcnma1−/− mice show normal expression of clock genes such as Arntl (Bmal1), indicating a role for BK channels in SCN pacemaker output, rather than in intrinsic time-keeping. Our findings implicate BK channels as important regulators of the SFR and suggest that the SCN pacemaker governs the expression of circadian behavioral rhythms through SFR modulation.
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Change history
03 August 2006
In the version of this article initially published, there was an error in the figure label of Figure 6d. The correct version of the figure is below. The error has been corrected in the HTML and PDF versions of the article.
Notes
*NOTE: In the version of this article initially published, there was an error in the figure label of Figure 6d. The correct version of the figure appears above. The error has been corrected in the HTML and PDF versions of the article.
References
King, D.P. & Takahashi, J.S. Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713–742 (2000).
Reppert, S.M. & Weaver, D.R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).
Hastings, M.H. & Herzog, E.D. Clock genes, oscillators, and cellular networks in the suprachiasmatic nuclei. J. Biol. Rhythms 19, 400–413 (2004).
Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).
Ueda, H.R. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192 (2005).
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).
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).
Ralph, M.R., Foster, R.G., Davis, F.C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).
Rusak, B. & Zucker, I. Neural regulation of circadian rhythms. Physiol. Rev. 59, 449–526 (1979).
Yamazaki, S., Kerbeshian, M.C., Hocker, C.G., Block, G.D. & Menaker, M. Rhythmic properties of the hamster suprachiasmatic nucleus in vivo. J. Neurosci. 18, 10709–10723 (1998).
Green, D.J. & Gillette, R. Circadian rhythm of firing rate recorded from single cells in the rat suprachiasmatic brain slice. Brain Res. 245, 198–200 (1982).
Groos, G. & Hendriks, J. Circadian rhythms in electrical discharge of rat suprachiasmatic neurones recorded in vitro. Neurosci. Lett. 34, 283–288 (1982).
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).
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).
Ikeda, M. et al. Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons. Neuron 38, 253–263 (2003).
Earnest, D.J. & Sladek, C.D. Circadian rhythms of vasopressin release from individual rat suprachiasmatic explants in vitro. Brain Res. 382, 129–133 (1986).
Shinohara, K., Honma, S., Katsuno, Y., Abe, H. & Honma, K. Circadian release of amino acids in the suprachiasmatic nucleus in vitro. Neuroreport 9, 137–140 (1998).
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).
Earnest, D.J., Digiorgio, S.M. & Sladek, C.D. Effects of tetrodotoxin on the circadian pacemaker mechanism in suprachiasmatic explants in vitro. Brain Res. Bull. 26, 677–682 (1991).
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).
Aton, S.J. & Herzog, E.D. Come together, right...now: synchronization of rhythms in a mammalian circadian clock. Neuron 48, 531–534 (2005).
Lundkvist, G.B. & Block, G.D. Role of neuronal membrane events in circadian rhythm generation. Methods Enzymol. 393, 623–642 (2005).
Itri, J.N., Michel, S., Vansteensel, M.J., Meijer, J.H. & Colwell, C.S. Fast delayed rectifier potassium current is required for circadian neural activity. Nat. Neurosci. 8, 650–656 (2005).
Kuhlman, S.J. & McMahon, D.G. Rhythmic regulation of membrane potential and potassium current persists in SCN neurons in the absence of environmental input. Eur. J. Neurosci. 20, 1113–1117 (2004).
de Jeu, M., Hermes, M. & Pennartz, C. Circadian modulation of membrane properties in slices of rat suprachiasmatic nucleus. Neuroreport 9, 3725–3729 (1998).
Zheng, B. et al. The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400, 169–173 (1999).
Antle, M.C., LeSauter, J. & Silver, R. Neurogenesis and ontogeny of specific cell phenotypes within the hamster suprachiasmatic nucleus. Brain Res. Dev. Brain Res. 157, 8–18 (2005).
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).
van den Pol, A.N. & Tsujimoto, K.L. Neurotransmitters of the hypothalamic suprachiasmatic nucleus: immunocytochemical analysis of 25 neuronal antigens. Neuroscience 15, 1049–1086 (1985).
Meredith, A.L., Thorneloe, K.S., Werner, M.E., Nelson, M.T. & Aldrich, R.W. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J. Biol. Chem. 279, 36746–36752 (2004).
Pittendrigh, C.S. & Daan, S. A Functional analysis of circadian pacemakers in nocturnal rodents. I. The stability and lability of spontaneous frequency. J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 106, 223–252 (1976).
Sokolove, P.G. & Bushell, W.N. The chi square periodogram: its utility for analysis of circadian rhythms. J. Theor. Biol. 72, 131–160 (1978).
Sausbier, M. et al. Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc. Natl. Acad. Sci. USA 101, 9474–9478 (2004).
Honma, S. et al. Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus. Biochem. Biophys. Res. Commun. 250, 83–87 (1998).
Low-Zeddies, S.S. & Takahashi, J.S. Chimera analysis of the Clock mutation in mice shows that complex cellular integration determines circadian behavior. Cell 105, 25–42 (2001).
Ceriani, M.F. et al. Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J. Neurosci. 22, 9305–9319 (2002).
Herzog, E.D., Takahashi, J.S. & Block, G.D. Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat. Neurosci. 1, 708–713 (1998).
Nakamura, W., Honma, S., Shirakawa, T. & Honma, K. Clock mutation lengthens the circadian period without damping rhythms in individual SCN neurons. Nat. Neurosci. 5, 399–400 (2002).
Albus, H. et al. Cryptochrome-deficient mice lack circadian electrical activity in the suprachiasmatic nuclei. Curr. Biol. 12, 1130–1133 (2002).
Yamaguchi, S. et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302, 1408–1412 (2003).
Kuhlman, S.J., Silver, R., Le Sauter, J., Bult-Ito, A. & McMahon, D.G. Phase resetting light pulses induce Per1 and persistent spike activity in a subpopulation of biological clock neurons. J. Neurosci. 23, 1441–1450 (2003).
Nitabach, M.N., Blau, J. & Holmes, T.C. Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock. Cell 109, 485–495 (2002).
Harmar, A.J. et al. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109, 497–508 (2002).
Cutler, D.J. et al. The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro. Eur. J. Neurosci. 17, 197–204 (2003).
Nitabach, M.N., Sheeba, V., Vera, D.A., Blau, J. & Holmes, T.C. Membrane electrical excitability is necessary for the free-running larval Drosophila circadian clock. J. Neurobiol. 62, 1–13 (2005).
Pitts, G.R., Ohta, H. & McMahon, D.G. Daily rhythmicity of large-conductance Ca(2+)-activated K(+) currents in suprachiasmatic nucleus neurons. Brain Res. 1071, 54–62 (2006).
Cloues, R.K. & Sather, W.A. Afterhyperpolarization regulates firing rate in neurons of the suprachiasmatic nucleus. J. Neurosci. 23, 1593–1604 (2003).
Misonou, H. et al. Immunolocalization of the Ca2+-activated K+ channel Slo1 in axons and nerve terminals of mammalian brain and cultured neurons. J. Comp. Neurol. 496, 289–302 (2006).
Rattray, M. & Michael, G.J. Oligonucleotide probes for in situ hybridization. in In Situ Hybridization: A Practical Approach 2nd edn. (ed. Wilkinson, D.G.) 23–67 (Oxford Univ. Press, Oxford, 1998).
Siepka, S.M. & Takahashi, J.S. Methods to record circadian rhythm wheel running activity in mice. Methods Enzymol. 393, 230–239 (2005).
Acknowledgements
We thank M. Barakat for assistance with circadian behavioral experiments, L. Baxter for assistance with animal care, and V. Cao for SCN slice preparation advice. We also thank D. Welsh for helpful comments on the manuscript. The work was supported by the Howard Hughes Medical Institute (R.W.A. & J.S.T.), the Mathers Foundation (R.W.A.) and the US National Institutes of Health (NIH MH-60385 to N.F.R.).
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Supplementary Table 1
Pearson r-squared values for the microarrays. Each probeset on each array was summarized by the median of the Perfect Match (PM) values. Reported is the Pearson correlation between the median values for each WT: Slo−/− pair of arrays in the data set. (PDF 40 kb)
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Meredith, A., Wiler, S., Miller, B. et al. BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output. Nat Neurosci 9, 1041–1049 (2006). https://doi.org/10.1038/nn1740
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DOI: https://doi.org/10.1038/nn1740
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