Anxiety-related mechanisms of respiratory dysfunction in a mouse model of Rett syndrome

• Published in: The Journal of neuroscience 2012-11, Vol.32 (48), p.17230-17240
• Main Authors: Ren, Jun, Ding, Xiuqing, Funk, Gregory D, Greer, John J
• Format: Article
• Language: English
• Subjects: Animals; Anxiety - genetics; Anxiety - physiopathology; Anxiety - psychology; Disease Models, Animal; Male; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Respiration; Respiration Disorders - genetics; Respiration Disorders - physiopathology; Respiration Disorders - psychology; Rett Syndrome - genetics; Rett Syndrome - physiopathology; Rett Syndrome - psychology; Wakefulness - physiology
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.2951-12.2012

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.