title: Anxiety-related mechanisms of respiratory dysfunction in a mouse model of Rett syndrome.
abstract: Rett syndrome (RTT) is a severe neurological disorder that is associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. RTT patients suffer from mental retardation and behavioral disorders, including heightened anxiety and state-dependent breathing irregularities, such as hyperventilation and apnea. Many symptoms are recapitulated by the Mecp2-null male mice (Mecp2(-/y)). To characterize developmental progression of the respiratory phenotype and explore underlying mechanisms, we examined Mecp2(-/y) and wild-type (WT) mice from presymptomatic periods to end-stage disease. We monitored breathing patterns of unrestrained mice during wake-sleep states and while altering stress levels using movement restraint or threatening odorant (trimethylthiazoline). Respiratory motor patterns generated by in situ working heart-brainstem preparations (WHBPs) were measured to assess function of brainstem respiratory networks isolated from suprapontine structures. Data revealed two general stages of respiratory dysfunction in Mecp2(-/y) mice. At the early stage, respiratory abnormalities were limited to wakefulness, correlated with markers of stress (increased fecal deposition and blood corticosterone levels), and alleviated by antalarmin (corticotropin releasing hormone receptor 1 antagonist). Furthermore, the respiratory rhythm generated by WHBPs was similar in WT and Mecp2(-/y) mice. During the later stage, respiratory abnormalities were evident during wakefulness and sleep. Also, WHBPs from Mecp2(-/y) showed central apneas. We conclude that, at early disease stages, stress-related modulation from suprapontine structures is a significant factor in the Mecp2(-/y) respiratory phenotype and that anxiolytics may be effective. At later stages, abnormalities of brainstem respiratory networks are a significant cause of irregular breathing patterns and central apneas.
authors.affiliation: Department of Physiology, Centre for Neuroscience, Women and Children's Health Research Institute, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Ding
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Funk
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012119:Respiration; D012120:Respiration Disorders / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D015518:Rett Syndrome / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D014851:Wakefulness / Q000502:physiology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2