Behavior Genetics

, Volume 31, Issue 5, pp 413–425 | Cite as

Magnesium Involvement in Sleep: Genetic and Nutritional Models

  • Didier Chollet
  • Paul Franken
  • Yvette Raffin
  • Jean-Georges Henrotte
  • Jean Widmer
  • Alain Malafosse
  • Mehdi Tafti


Alterations of peripheral magnesium (Mg) concentration have been reported in association with several behavioral disorders and sleep organization. Blood Mg regulation is under a strong genetic control, whereas brain Mg regulation does not seem to be affected. We have studied peripheral and central levels of Mg and analyzed sleep in two lines of mice selected for low (MGL) and high (MGH) red blood cell (RBC) Mg levels. The same variables were also studied in C57BL/6J mice before and after 3 weeks of Mg deficiency. Whereas blood Mg was highly affected by the selection, brain Mg exhibited only small differences between the two lines. In contrast, Mg deficiency strongly decreased both central and peripheral Mg levels. Sleep analysis indicated that in both models the amount of paradoxical sleep was lower in mice with higher Mg levels. The amplitude of daily variation in sleep and slow-wave sleep delta power was markedly decreased in MGH line. Quantitative electroencephalogram (EEG) analysis also revealed a faster theta peak frequency in MGH mice, irrespective of behavioral states. Central Mg showed significant correlations with the amount of paradoxical sleep and sleep consolidation. However, because the direction of these correlations was not consistent, it is concluded that optimal, (physiological) rather than high or low, Mg levels are needed for normal sleep regulation.

MGL and MGH mice brain blood paradoxical sleep theta, EEG 


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  1. Altura, B. M., Gebrewold, A., Zhang, A., Altura B. T., and Gupta, R. K. (1997). Short-term reduction in dietary intake of magnesium causes deficits in brain intracellular free Mg2+ and [H+]i but not high-energy phosphates as observed by in vivo 31P-NMR. Biochimica. Biophysica. Acta. 1358: 1–5.Google Scholar
  2. Archer, W. H., Emerson, R. L., and Reusach, C. S. (1972). Intra-and extracellular fluid magnesium by atomic absorption spectrophotometry. Clin. Biochem. 5: 159–161.PubMedGoogle Scholar
  3. Aymard, N., Leyris, A., Monier, C., Francès, H., Boulu, R., and Henrotte, J-G. (1995). Brain catecholamines, serotonin and their metabolites in mice selected for low (MGL) and high (MGH) blood magnesium levels. Magnes. Res. 8: 5–9.PubMedGoogle Scholar
  4. Bac, P., Maurois, P., Dupont, C., Pages, N., Stables, J. P., Gressens, P., Evrard, Ph., and Vamecq, J. (1998). Magnesium deficiencydependent audiogenic seizures (MDDASs) in adult mice: A nutritional model for discriminatory screening of anticonvulsant drugs and original assessment of neuroprotection properties. J. Neurosci. 18: 4363–4373.PubMedGoogle Scholar
  5. Belknap, J. K., Berg, J. H., Cocke, R., and Clancy, A. N. (1977). Induction and reversal of the magnesium deficiency syndrome in inbred mice. Exp. Neurol. 57: 506–515.PubMedGoogle Scholar
  6. Boadle-Biber, M. C. (1978). Activation of tryptophan hydroxylase from central serotonergic neurons by calcium and depolarization. Biochem. Pharmacol. 27: 1069–1079.PubMedGoogle Scholar
  7. Boutrel, B., France, B., Hen, R., Hammon, M., and Adrian, J. (1999). Key role of 5-HT1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knock-out mice. J. Neurosci. 19: 3204–3212.PubMedGoogle Scholar
  8. Chollet, D., Franken, P., Raffin, Y., Malafosse, A., Widmer, J., and Tafti, M. (2000a). Blood and brain magnesium in inbred mice and their correlation with sleep quality. Am. J. Physiol. 279: R2173-R2178.Google Scholar
  9. Chollet, D., Steimer, Th., Tafti, M., and Widmer, J. (2000b). Behavioral differences between two lines of mice genetically selected for high (MGH) or low (MGL) blood magnesium levels: Is there a link between magnesium and anxiety or depression? Mag. 2000: 165.Google Scholar
  10. Chuang, H-U., Jan, Y. N., and Jan, L. Y. (1997). Regulation of IRK3 inward rectifier K1 channel by M1 acetylcholine receptor and intracellular magnesium. Cell 89: 1121–1132.PubMedGoogle Scholar
  11. Chutkow, J. G. (1972). Distribution of magnesium and calcium in brains of normal and magnesium-deficient rats. Mayo. Clin. Proc. 47: 647–653.PubMedGoogle Scholar
  12. Chutkow, J. G. (1990). Magnesium and the central nervous system: Metabolism, neurophysiological functions, and clinical disorders. In: Metal Ions in Biological Systems: Compendium on Magnesium and its Role in Biology, Nutrition, and Physiology, H. Sigel and A. Sigel (Eds.), New York: Marcel Dekker, pp. 441–461.Google Scholar
  13. Classen, H. G. (1986). Systemic stress, magnesium status and cardiovascular damage. Magnesium 5: 105–110.PubMedGoogle Scholar
  14. Crochet, S., and Sakai, K. (1999). Effects of microdialysis application of monoamines on the EEG and behavioral states in the cat mesopontine tegmentum. Eur. J. Neurosci. 11: 3738–3752.PubMedGoogle Scholar
  15. Darlu, P., Rao, D. C., Henrotte, J-G., and Lalouel, J-M. (1982). Genetic regulation of plasma and red blood cell magnesium concentrations in man: I. Univariate and bivariate path analyses. Am. J. Hum. Genet. 34: 874–887.PubMedGoogle Scholar
  16. Depoorter, H., Françon, D., and Llopis, J. (1993). Effects of magnesium-deficient diet on sleep organization in rats. Neuropsychobiology 24: 237–245.Google Scholar
  17. Dralle, D., and Bödeker, R. H. (1980). Serum magnesium level and sleep behavior of newborn infants. Eur. J. Pediat. 134: 239–243.Google Scholar
  18. Feillet-Coudray, C., Mazur, A., Coudray, C., Henrotte, J-G., and Rayssiguier, Y. (2000). Magnesium status evaluation in mice selected for high and low erythrocyte magnesium levels. Mag. 2000: 58.Google Scholar
  19. Franken, P., Malafosse, A., and Tafti, M. (1998). Genetic variation in EEG activity during sleep in inbred mice. Am. J. Physiol. 275: R1127-R1137.PubMedGoogle Scholar
  20. Franken, P., Malafosse, A., and Tafti, M. (1999). Genetic determinants of sleep regulation in inbred mice. Sleep 22: 155–169.PubMedGoogle Scholar
  21. Franken, P., Chollet, D., and Tafti, M. (2001). The homeostatic regulation of sleep need is under genetic control. J. Neurosci. 21: 2610–2621.PubMedGoogle Scholar
  22. Franken, P., Lopez-Molina, L., Marcacci, L., Schibler, U., and Tafti, M. (2000). The transcription factor DBP affects circandian sleep consolidation and rhythmic EEG activity. J. Neurosci. 20: 617–625.PubMedGoogle Scholar
  23. Franklin, K. B. J., and Paxinos, G. (1997). The mouse brain in stereotaxic coordinates. New York: Academic Press.Google Scholar
  24. Fujise, H., Cruz, P., Reo, N. V., and Lauf, P. K. (1991). Relationship between total magnesium concentration and free intracellular magnesium in sheep red blood cells. Biochim. Biophys. Acta. 1094: 51–54.PubMedGoogle Scholar
  25. Hallak, M., Berman, R. F., and Irtenkauf, S. M. (1992). Peripheral magnesium sulfate enters the brain and increases the threshold for hippocampal seizures in rats. Am. J. Obstet. Gynecol. 167: 1605–1610.PubMedGoogle Scholar
  26. Hallak, M., Horta, J. W., Custodio, D., and Kruger, M. L. (2000). Magnesium prevents seizure-induced reduction in excitatory amino acid receptor (kainate and alpha-amino-3-hydroxy-5-methylisoxazol-4-propionic acid) binding in pregnant rat brain. Am. J. Obstet. Gynecol. 183: 793–798.PubMedGoogle Scholar
  27. Heffner, T. G., Hartman, J. A., and Seiden, L. S. (1980). A rapid method for the regional dissection of the rat brain. Pharmac. Biochem. Behav. 13: 453–456.Google Scholar
  28. Henrotte, J-G. (1993). Genetic regulation of cellular magnesium content. In Magnesium and the cell, N. J. Birch (Ed.), London: Academic Press, pp. 177–195.Google Scholar
  29. Henrotte, J-G., Colombani, J., Pineau, M., and Dausset, J. (1984). Role of H-2 and non H-2 genes in the control of blood magnesium levels. Immunogenetics 19: 435–448.PubMedGoogle Scholar
  30. Henrotte, J-G., Pla, M., and Dausset, J. (1990). HLA-and H-2-associated variations of intra-and extracellular magnesium content. Proc. Natl. Acad. Sci. USA 87: 1894–1898.PubMedGoogle Scholar
  31. Henrotte, J-G., Aymard, N., Leyris, A., Monier, C., Francès, H., and Boulu, R. (1993). Brain weight and noradrenaline content in mice selected for low (MGL) and high (MGH) blood magnesium. Magnes. Res. 6: 21–24.PubMedGoogle Scholar
  32. Henrotte, J-G., Aymard, N., Allix, M., and Boulu, R. G. (1995). Effect of pyridoxine and magnesium on stress-induced gastric ulcers in mice selected for low or high blood magnesium levels. Ann. Nutr. Metab. 39: 285–290.PubMedGoogle Scholar
  33. Henrotte, J-G., Franck, G., Santarromana, M., Francès, H., Mouton, D., and Motta, R. (1997). Mice selected for low and high blood magnesium levels: A new model for stress studies. Physiol. Behav. 61: 653–658.PubMedGoogle Scholar
  34. Jouvet, M. (1962). Recherches sur les structures nerveuses et les mécanismes responsables des differentes phases du sommeil physiologique. [in French] Arch. Ital. Biol. 100: 125–206.PubMedGoogle Scholar
  35. Kantak, K. M. (1988). Magnesium deficiency alters aggressive behavior and catecholamine function. Behav. Neurosci. 102: 304–311.PubMedGoogle Scholar
  36. Kirov, G. K., and Tsachev, K. N. (1990). Magnesium, schizophrenia and manic-depressive disease. Neuropsychobiology 23: 79–81.PubMedGoogle Scholar
  37. Kuner, T., and Schoepfer, R. (1996). Multiple structural elements determine subunit specificity of Mg21 block in NMDA receptor channels. J. Neurosci. 16: 3549–3558.PubMedGoogle Scholar
  38. Li-Smerin, Y., and Johnson, J. W. (1996a). Effects of intracellular Mg2+ on channel gating and steady-state responses of the NMDA receptor in cultured rat neurons. J. Physiol. (Lond.) 491: 137–150.Google Scholar
  39. Li-Smerin, Y., and Johnson, J. W. (1996b). Kinetics of the block by intracellular Mg21 of the NMDA-activated channel in cultured rat neurons. J. Physiol. (Lond.) 491: 121–135.Google Scholar
  40. Lopez-Molina, L., Conquet, F., Dubois-Dauphin, M., and Schibler, U. (1997). The DBP gene is expressed according to a circadian rhythm in the SCN and influences circadian behavior. EMBO J. 16: 6762–6771.PubMedGoogle Scholar
  41. Matsuda, H., Saigusa, A., and Irisawa, H. (1987). Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+. Nature 325: 156–159.PubMedGoogle Scholar
  42. McNaughton, N., and Sedgewick, E. M. (1978). Reticular stimulation and hippocampal theta rhythm in rats: Effects of drugs. Neuroscience 3: 629–632.PubMedGoogle Scholar
  43. Modak, A. T., Montanez, J., and Stavinoha, W. B. (1979). Magnesium deficiency: Brain acetylcholine and motor activity. Neurobehav. Toxicol. 1: 187–191.Google Scholar
  44. Motta, R., and Louis, J. P. (1999). Audiogenic seizure sensitivity in mouse lines genetically selected for high versus low blood magnesium levels. Behav. Genet. 29: 125–130.PubMedGoogle Scholar
  45. Nelson, D. L., Herbet, A., Enjalbert, A., Bockaert, J., and Hamon, M. (1980). Serotonin-sensitive adenylate cyclase and (3H) serotonin binding sites in the CNS of the rat. Biochem. Pharmacol. 29: 2445–2543.PubMedGoogle Scholar
  46. Nuytten, D., Van Hees, J., Meulemans, A., and Carton, H. (1991). Magnesium deficiency as a cause of acute intractable seizures. J. Neurol. 238: 262–264.PubMedGoogle Scholar
  47. Okada, M., and Kaneko, S. (1998). Pharmacological interactions between magnesium ion and adenosine on monoaminergic system in the central nervous system. Magnes. Res. 11: 289–305.PubMedGoogle Scholar
  48. Poenaru, S., Rouhani, S., Durlach, J., Aymard, N., Rayssiguier, Y., and Iovino, M. (1984). Vigilance states and cerebral monoamine metabolism in experimental magnesium deficiency. Magnesium 3: 145–151.PubMedGoogle Scholar
  49. Popoviciu, L., Bagathai, J., Buksa, C., Delast-Popoviciu, D., Bicher, G., Delast-Popoviciu, R., Covaciu, S., and Szalay, E. (1991). Clinical and polysomnographic researches in patients with sleep disorders associated with magnesium deficiencies. In Magnesium: A Relevant Ion. B. Lasserre and J. Durlach (Eds.), London: John Libbey, pp. 353–365.Google Scholar
  50. Resnick, L. M., Gupta, R. K., and Laragh, J. H. (1984). Intracellular free magnesium in erythrocytes of essential hypertension: Relation to blood pressure and serum divalent cations. Proc. Natl. Acad. Sci. USA 81: 6511–6515.PubMedGoogle Scholar
  51. Sakai, K. (1988). Executive mechanisms of paradoxical sleep. Arch. Ital. Biol. 126: 239–257.PubMedGoogle Scholar
  52. Siegel, J. M. (1989). Brainstem mechanisms generating REM sleep. In Principles and Practice of Sleep Medicine, M. H. Kryger, T. Roth, and W. C. Dement (Eds.), Philadelphia: Saunders, pp. 104–120.Google Scholar
  53. Tafti, M., Malafosse, A., and Franken, P. (1998). Genetic determinants of theta rhythm in mice. J. Sleep Res. 7(Suppl 2): 269.Google Scholar
  54. Touitou, Y., Touitou, C., Bogdan, A., Reinberg, A., Motohashi, Y., Auzéby, A., and Beck, H. (1989). Circadian and seasonal variations of electrolytes in aging humans. Clinica Chimica Acta. 180: 245–254.Google Scholar
  55. Usdin, T. B., Creese, I., and Synder, S. H. (1980). Regulation by cations by (3H) spiroperidol binding associated with dopamine receptors of rat brain. J. Neurochem. 34: 669–676.PubMedGoogle Scholar
  56. Vertes, R. P. (1981). An analysis of ascending brainstem systems involved in hippocampal synchronization and desynchronization. J. Neurophysiol. 46: 1140–1159.PubMedGoogle Scholar
  57. Vertes, R. P., and Kocsis, B. (1997). Brainstem-diencephalo-septohippocampal systems controlling the theta rhythm of the hippocampus. Neuroscience 81: 893–926.PubMedGoogle Scholar
  58. Vinogradova, O. S. (1995). Expression, control, and probable functional significance of the neuronal theta-rhythm. Prog. Neurobiol. 445: 523–583.Google Scholar
  59. Widmer, J., Henrotte, J-G., Raffin, Y., Bovier, Ph., Hilleret, H., and Gaillard, J-M. (1995). Relationship between erythrocyte magnesium, plasma electrolytes and cortisol, and intensity of symptoms in major depressed patients. J. Affect. Disord. 34: 201–209.PubMedGoogle Scholar
  60. Widmer, J., Henrotte, J-G., Raffin, Y., Mouthon, D., Chollet, D., Stépanian, R., and Bovier, Ph. (1998). Relationship between blood magnesium and psychomotor retardation in drug-free patients with major depression. Eur. Psychiatry 13: 90–97.Google Scholar
  61. Wollmuth, L. P., Kuner, T., and Sakmann, B. (1998). Intracellular Mg2+ interacts with structural determinants of the narrow constriction contributed by the NR1-subunit in the NMDA receptor channel. J. Physiol. (Lond.) 506: 33–52.Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Didier Chollet
    • 1
  • Paul Franken
    • 1
  • Yvette Raffin
    • 1
  • Jean-Georges Henrotte
    • 2
  • Jean Widmer
    • 1
  • Alain Malafosse
    • 1
  • Mehdi Tafti
    • 1
  1. 1.Biochemistry and Clinical Neurophysiology, Department of PsychiatryUniversity of GenevaGenevaSwitzerland
  2. 2.Institut de Chimie des Substances NaturellesCNRSGif-sur-YvetteFrance

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