title: Altered responses of MeCP2-deficient mouse brain stem to severe hypoxia.
abstract: Rett syndrome (RTT) patients suffer from respiratory arrhythmias with frequent apneas causing intermittent hypoxia. In a RTT mouse model (methyl-CpG-binding protein 2-deficient mice; Mecp2(-/y)) we recently discovered an enhanced hippocampal susceptibility to hypoxia and hypoxia-induced spreading depression (HSD). In the present study we investigated whether this also applies to infant Mecp2(-/y) brain stem, which could become life-threatening due to failure of cardiorespiratory control. HSD most reliably occurred in the nucleus of the solitary tract (NTS) and the spinal trigeminal nucleus (Sp5). HSD susceptibility of the Mecp2(-/y) NTS and Sp5 was increased on 8 mM K(+)-mediated conditioning. 5-HT(1A) receptor stimulation with 8-hydroxy-2-(di-propylamino)tetralin (8-OH-DPAT) postponed HSD by up to 40%, mediating genotype-independent protection. The deleterious impact of HSD on in vitro respiration became obvious in rhythmically active slices, where HSD propagation into the pre-Bötzinger complex (pre-BötC) immediately arrested the respiratory rhythm. Compared with wild-type, the Mecp2(-/y) pre-BötC was invaded less frequently by HSD, but if so, HSD occurred earlier. On reoxygenation, in vitro rhythms reappeared with increased frequency, which was less pronounced in Mecp2(-/y) slices. 8-OH-DPAT increased respiratory frequency but failed to postpone HSD in the pre-BötC. Repetitive hypoxia facilitated posthypoxic recovery only if HSD occurred. In 57% of Mecp2(-/y) slices, however, HSD spared the pre-BötC. Although this occasionally promoted residual hypoxic respiratory activity ("gasping"), it also prolonged the posthypoxic recovery, and thus the absence of central inspiratory drive, which in vivo would lengthen respiratory arrest. In view of the breathing disorders in RTTs, the increased hypoxia susceptibility of MeCP2-deficient brain stem potentially contributes to life-threatening disturbances of cardiorespiratory control.
authors.affiliation: Deutsche Forschungsgemeinschaft Research Center for Molecular Physiology of the Brain, Zentrum für Physiologie und Pathophysiologie, Abteilung Neuro- und Sinnesphysiologie, Georg-August-Universität Göttingen, Göttingen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kron
authors.forename: Jasper L
authors.initials: JL
authors.lastname: Zimmermann
authors.forename: Mathias
authors.initials: M
authors.lastname: Dutschmann
authors.forename: Frank
authors.initials: F
authors.lastname: Funke
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000473:pathology / Q000503:physiopathology*; D013181:Cortical Spreading Depression / Q000187:drug effects / Q000235:genetics*; D004558:Electric Stimulation; D045604:Extracellular Fluid / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D012125:Respiratory Center / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017552:Solitary Nucleus / Q000503:physiopathology; D013997:Time Factors; D014279:Trigeminal Nucleus, Spinal / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011188:Potassium