title: Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice.
abstract: 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 approximately 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 approximately 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.
authors.affiliation: Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Viemari
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Roux
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Tryba
authors.forename: Véronique
authors.initials: V
authors.lastname: Saywell
authors.forename: Henri
authors.initials: H
authors.lastname: Burnet
authors.forename: Fernando
authors.initials: F
authors.lastname: Peña
authors.forename: Sébastien
authors.initials: S
authors.lastname: Zanella
authors.forename: Michelle
authors.initials: M
authors.lastname: Bévengut
authors.forename: Magali
authors.initials: M
authors.lastname: Barthelemy-Requin
authors.forename: Laura B K
authors.initials: LB
authors.lastname: Herzing
authors.forename: Anne
authors.initials: A
authors.lastname: Moncla
authors.forename: Josette
authors.initials: J
authors.lastname: Mancini
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.forename: Gérard
authors.initials: G
authors.lastname: Hilaire
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008526:Medulla Oblongata / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015656:Respiratory Mechanics / Q000235:genetics / Q000502:physiology; D015619:Respiratory System Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009638:Norepinephrine