Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2-/y knockout mice

J Physiol. 2007 Mar 15;579(Pt 3):863-76. doi: 10.1113/jphysiol.2006.119966. Epub 2007 Jan 4.


Rett syndrome (RTT) is an inborn neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 gene (MECP2). Besides mental retardation, most patients suffer from potentially life-threatening breathing arrhythmia. To study its pathophysiology, we performed comparative analyses of the breathing phenotype of Mecp2-/y knockout (KO) and C57BL/6J wild-type mice using the perfused working heart-brainstem preparation (WHBP). We simultaneously recorded phrenic and efferent vagal nerve activities to analyse the motor pattern of respiration, discriminating between inspiration, postinspiration and late expiration. Our results revealed respiratory disturbances in KO preparations that were similar to those reported from in vivo measurements in KO mice and also to those seen in RTT patients. The main finding was a highly variable postinspiratory activity in KO mice that correlated closely with breathing arrhythmias leading to repetitive apnoeas even under undisturbed control conditions. Analysis of the pontine and peripheral sensory regulation of postinspiratory activity in KO preparations revealed: (i) prolonged apnoeas associated with enhanced postinspiratory activity after glutamate-induced activation of the pontine Kölliker-Fuse nucleus; and (ii) prolonged apnoeas and lack of reflex desensitization in response to repetitive vagal stimulations. We conclude that impaired network and sensory mediated synaptic control of postinspiration induces severe breathing dysfunctions in Mecp2-/y KO preparations. As postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway-related clinical problems of patients with RTT such as apnoeas, loss of speech and weak coordination of breathing and swallowing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Electric Stimulation
  • Exhalation / physiology*
  • Genotype
  • Glutamic Acid / pharmacology
  • Inhalation / physiology*
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Methyl-CpG-Binding Protein 2 / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microinjections
  • Phenotype
  • Pons / drug effects
  • Pons / physiology*
  • Respiratory Insufficiency / genetics
  • Respiratory Insufficiency / physiopathology*
  • Rett Syndrome / genetics
  • Rett Syndrome / physiopathology*
  • Vagus Nerve / physiology
  • X Chromosome


  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Glutamic Acid