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Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei

Authors

  • Eiko Iwahana,

    1. Department of Pharmacology, School of Science and Engineering, Waseda University, 2-7-5 Higashi-Fushimi, Nishi-Tokyo, Tokyo 202-0021, Japan
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  • Masashi Akiyama,

    1. Department of Pharmacology, School of Science and Engineering, Waseda University, 2-7-5 Higashi-Fushimi, Nishi-Tokyo, Tokyo 202-0021, Japan
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    • *

      Present address: Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0032, Japan

  • Kazuko Miyakawa,

    1. Department of Pharmacology, School of Science and Engineering, Waseda University, 2-7-5 Higashi-Fushimi, Nishi-Tokyo, Tokyo 202-0021, Japan
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  • Ayumi Uchida,

    1. Department of Pharmacology, School of Science and Engineering, Waseda University, 2-7-5 Higashi-Fushimi, Nishi-Tokyo, Tokyo 202-0021, Japan
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  • Jiro Kasahara,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
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  • Kohji Fukunaga,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
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  • Toshiyuki Hamada,

    1. Advanced Research Center for Human Sciences, Waseda University, Tokorozawa, Saitama 359-1192, Japan
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    • Present address: Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan

  • Shigenobu Shibata

    1. Department of Pharmacology, School of Science and Engineering, Waseda University, 2-7-5 Higashi-Fushimi, Nishi-Tokyo, Tokyo 202-0021, Japan
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: Dr Shigenobu Shibata, as above.
E-mail: shibatas@waseda.jp

Abstract

A circadian clock located in the suprachiasmatic nucleus (SCN) regulates the period of physiological and behavioural rhythms to approximately 24 h. Lithium can lengthen the period of circadian rhythms in most organisms although little is known about the underlying mechanism. In the present study, we examined Drosophila shaggy ortholog glycogen synthase kinase-3 (GSK-3) protein expression in the SCN after lithium treatment. When locomotor activity was assessed, we found an association between the effect of lithium and the period of circadian oscillation as well as the level of GSK-3 protein expression. The decreased expression of GSK-3 and increased expression of phosphorylated GSK-3 (pGSK-3) resulted in an antiphasic circadian rhythm between the two in the SCN of lithium-treated mice housed under both light–dark and constant dark conditions. The enzyme activity of GSK-3 in the SCN was low when the level of pGSK-3 protein was high, as examined by immunoblotting analysis. Thus, GSK-3 enzyme activity has a correlation with the expression of GSK-3 protein in the SCN. Although both GSK-3 and pGSK-3 proteins are also expressed in the arcuate nucleus, lithium did not affect their expression. Based on the association that we found between lengthened circadian period and GSK-3 protein and GSK-3 activity in the SCN, we suggest that GSK-3 plays a role in regulating the period of the mammalian circadian pacemaker.

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