Noenatal obstructive sleep apneas in a mouse model of Down syndrome

Introduction

Down syndrome (DS) is a genetic disease caused by a third copy of chromosome 21, leading to various physical features, developmental and cognitive delays and intellectual disability. In neonates, main symptoms concern congenital heart defects, gastrointestinal abnormalities and sleep disordered breathing. A recent retrospective study showed a high prevalence of obstructive sleep apnea (OSA) in children with DS, with severity inversely related with age culminating at 58% of severe OSA in neonates < 1y. Knowing that OSA can cause intermittent hypoxia and hypercapnia and have detrimental effects on health and development, it raises concerns about the impact of OSA on neurodevelopmental disorders associated with DS, especially in neonates. Many animal models exist. Dp(16)1Yey mice, a genetically engineered model, exhibit cognitive impairments and characteristics associated with OSA, including craniofacial hypoplasia and reduced upper airway volume at adult age. To further investigate the contribution of respiratory-related disorders to DS pathophysiology, we examined the respiratory phenotype of Dp(16)1Yey mice at birth, with special attention to central, obstructive and mixed apneas.

Methods

On the day of birth, the pups’ snouts were attached to a pneumotachometer with a polyether adhesive. Abdominal movements were measured using a laser sensor pointing the lateral abdominal wall to detect respiratory efforts and discriminate apnea. The classification into central, obstructive or mixed apneas was performed by visual inspection of pneumotachometer and laser signals. Electrocardiograms (ECG) were recorded using two human skin electrodes adapted to the size of the pups. Heart rate (HR) was determined from the R-R wave peaks after visual selection of continuous, 20-s or longer ECG segments with clearly defined QRS waves.

Results

At birth, Dp(16)1Yey mouse pups exhibited lower weight and HR compared to their wild type (WT) counterparts. Baseline breathing variables and response to hypercapnia were similar between the two groups. Total time for obstructive apneas was longer in Dp(16)1Yey than in WT pups (2.18 ± 1.8 s/min vs. 1.24 ± 1.6 s/min, respectively; P = 0.023), owing to their longer mean duration (3.11 ± 1.1 s vs. 2.05 ± 0.7 s, respectively; P = 0.002). ECG analysis did not reveal apnea-related bradycardia in either group.

Conclusion

These findings highlight the relevance of the Dp(16)1Yey model for studying OSA in DS, including its occurrence at birth. This model represents a valuable tool to investigate the contribution of early respiratory disorders to DS pathology and assess safety and efficacy of pharmacological treatments targeting obstructive sleep disordered breathing in DS.