Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice
Por:
Viemari J.-C., Roux J.-C., Tryba A.K., Saywell V., Burnet H., Peña F., Zanella S., Bévengut M., Barthelemy-Requin M., Herzing L.B.K., Moncla A., Mancini J., Ramirez J.-M., Villard L., Hilaire G.
Publicada:
1 ene 2005
Resumen:
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. Copyright © 2005 Society for Neuroscience.
Filiaciones:
Viemari J.-C.:
Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, United States
Roux J.-C.:
Institut National de la Santé et de la Recherche Médicale, Faculté De Médecine de la Timone, Université de La Méditerrannée, 13385 Marseille Cedex 5, France
Tryba A.K.:
Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, United States
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Saywell V.:
Institut National de la Santé et de la Recherche Médicale, Faculté De Médecine de la Timone, Université de La Méditerrannée, 13385 Marseille Cedex 5, France
Burnet H.:
Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2722, Université de La Méditerrannée, 13009 Marseille, France
Peña F.:
Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, United States
Departamento de Farmacobiología, Centro de Investigación Y Estudios Avanzados, 14330 Mexico Distrito Federal, Mexico
Zanella S.:
Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2722, Université de La Méditerrannée, 13009 Marseille, France
Bévengut M.:
Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2722, Université de La Méditerrannée, 13009 Marseille, France
Barthelemy-Requin M.:
Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2722, Université de La Méditerrannée, 13009 Marseille, France
Herzing L.B.K.:
Northwestern University Feinberg School of Medicine, Program in Human and Molecular Genetics, Children's Memorial Institute for Education and Research, Chicago, IL 60614, United States
Moncla A.:
Institut National de la Santé et de la Recherche Médicale, Faculté De Médecine de la Timone, Université de La Méditerrannée, 13385 Marseille Cedex 5, France
Mancini J.:
Département de Neurologie Pédiatrique, Hôpital d'Enfants de la Timone, 13385 Marseille Cedex 5, France
Ramirez J.-M.:
Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, United States
Department of Organismal Biology and Anatomy, University of Chicago, 1027 East 57th Street, Chicago, IL 60637, United States
Villard L.:
Institut National de la Santé et de la Recherche Médicale, Faculté De Médecine de la Timone, Université de La Méditerrannée, 13385 Marseille Cedex 5, France
Hilaire G.:
Centre National de la Recherche Scientifique, Formation de Recherche en Evolution 2722, Université de La Méditerrannée, 13009 Marseille, France
All Open Access, Bronze
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