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Received August 28, 2006
Revised October 16, 2006
Accepted after revision January 2, 2007
1 Georg August University Göttingen, Germany
2 Georg August University G&ttingen & DFG Research Center Molecular Physiology of the Brain, Germany
* To whom correspondence should be addressed. E-mail: mdutsch{at}gwdg.de.
The 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, (ii) prolonged apnoeas and lacking reflex desensitisation 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. Since postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway related clinical problems of RTT patients such as apnoeas, loss of speech and the weak coordination of breathing and swallowing.
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