Physiological definition of upper airway obstructions in mouse model for Rett syndrome

Rett syndrome is a neuro-developmental disease accompanied by breathing symptoms including breath-hold events, and is caused by mutation of the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Males of Mecp2-deficient mice (Mecp2(-/y)) also develop breathing symptoms, with erratic rhythm and life-threatening apnoeas from postnatal day 30 (P30), leading to respiratory distress and premature death at around P60. We investigated the respiratory function of conscious Mecp2(-/y) mice at P40-P60 using conventional whole-body plethysmography, double-chamber plethysmography and chest EMG recordings. Double-chamber plethysmography revealed a persistent increase in respiratory work-load with enlarged chest movements, but no subsequent increase of tidal volume thus revealing a mismatch between airflow and muscle work-load. Apnoeas occurred with cessation of both chest movements and ventilation, but some (40%) developed with persisting rhythmic chest EMG discharges or chest movements without respiratory airflow, suggesting respiratory efforts against obstructed airways. Airway obstruction was maintained even when the respiratory drive increased significantly, triggering large chest EMG discharges and movements. Whole-body plethysmography of Mecp2(-/y) mice revealed significant increases of spirograms, reflecting forced chest movements against partially obstructed airways. The persisting chest EMG discharges and rhythmic chest movements without respiratory airflow suggest that Mecp2 inactivation alters neural circuits controlling the upper airway dilator muscles. The observed breath-hold events in Mecp2(-/y) mice might imply disturbance of neural circuits attached to voluntary control of breathing.