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The Journal of Neuroscience, December 14, 2005, 25(50):11521-11530; doi:10.1523/JNEUROSCI.4373-05.2005

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Neurobiology of Disease
Mecp2 Deficiency Disrupts Norepinephrine and Respiratory Systems in Mice

Jean-Charles Viemari,1 * Jean-Christophe Roux,2 * Andrew K. Tryba,1,7 Véronique Saywell,2 Henri Burnet,3 Fernando Peña,1,4 Sébastien Zanella,3 Michelle Bévengut,3 Magali Barthelemy-Requin,3 Laura B. K. Herzing,5 Anne Moncla,2 Josette Mancini,6 Jan-Marino Ramirez,1 Laurent Villard,2 and Gérard Hilaire3

1Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois 60637, 2Institut National de la Santé et de la Recherche Médicale, Unité 491, Facultéde Médecine de la Timone, Universitédela Méditerrannée, 13385 Marseille Cedex 5, France, 3Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2722, Groupe d'Etude des Réseaux Moteurs, Universitédela Méditerrannée, 13009 Marseille, France, 4Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados, 14330 Mexico Distrito Federal, Mexico, 5Northwestern University Feinberg School of Medicine, Program in Human and Molecular Genetics, Children's Memorial Institute for Education and Research, Chicago, Illinois 60614, 6Département de Neurologie Pédiatrique, Hôpital d'Enfants de La Timone, 13385 Marseille Cedex 5, France, and 7Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We used in vivo plethysmography, in vitro electrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of the MECP2 mutation on breathing in wild-type (wt) and Mecp2-deficient (Mecp2-/y) mice. At birth, Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At ~1 month of age, most Mecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even in Mecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetized Mecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at ~2 months of age. During their last week of life, Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content. In vitro experiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular in Mecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances in Mecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.

Key words: Mecp2 gene; respiration; norepinephrine; A1/C1 neurons; A2/C2 neurons; Rett syndrome

Received April 6, 2005; revised October 13, 2005; accepted October 22, 2005.






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