Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2-/y knockout mice.
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.
Stettner
Georg M
GM
Department of Pediatrics and Pediatric Neurology, Georg August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Huppke
Peter
P
Brendel
Cornelia
C
Richter
Diethelm W
DW
Gärtner
Jutta
J
Dutschmann
Mathias
M
D000818:Animals; D004558:Electric Stimulation; D045853:Exhalation / Q000502:physiology*; D005838:Genotype; D018698:Glutamic Acid / Q000494:pharmacology; D001239:Inhalation / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D010641:Phenotype; D011149:Pons / Q000187:drug effects / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000235:genetics / Q000503:physiopathology*; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology*; D014630:Vagus Nerve / Q000502:physiology; D014960:X Chromosome
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D018698:Glutamic Acid