Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice.
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.
Viemari
Jean-Charles
JC
Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, Illinois 60637, USA.
Roux
Jean-Christophe
JC
Tryba
Andrew K
AK
Saywell
Véronique
V
Burnet
Henri
H
Peña
Fernando
F
Zanella
Sébastien
S
Bévengut
Michelle
M
Barthelemy-Requin
Magali
M
Herzing
Laura B K
LB
Moncla
Anne
A
Mancini
Josette
J
Ramirez
Jan-Marino
JM
Villard
Laurent
L
Hilaire
Gérard
G
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
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009638:Norepinephrine