Categorization of sleep apneas in different mouse models of human diseases

Introduction. Sleep apnea is a common breathing disorder. Apneas are categorized, based on the origin, as central (CSA), when there is an impaired transmission of the signal for inspiration, or as obstructive (OSA), when an airway obstruction occurs. This condition is prevalent in patients with Down Syndrome (DS), CDKL5 deficiency disorder (CDD), and Pierre Robin sequence (PRS). Therefore, we investigate whether the mouse models of DS (Ts65Dn mice, TS), CDD (CDKL5-knockout mice, CDKL5-KO), and PRS (BMP7-knockout, BMP7-KO mice) could replicate the respiratory disturbances observed in human patients. Methods. Experiments were performed on 12 TS mice and 14 euploid controls (EU) for the model of DS, 14 CDKL5-KO and 10 wild-type mice (CDKL5-WT) for the model of CDD, and 3 BMP7-KO and 3 control mice (BMP7-WT) for the model of PRS. Each mouse was implanted with specific electrodes for sleep stage discrimination and diaphragmatic activity (DIA) detection and was recorded inside a whole-body plethysmograph (WBP) for 8 hours during the light (resting) period. Sleep and respiratory phenotypes were assessed and apneas occurring during sleep were categorized as either CSA or OSA based on DIA and WBP signals. Results. TS mice had a decreased occurrence rate of CSA during non-rapid-eye-movement sleep (NREMS) and a higher occurrence rate of apneas with an obstructive component during rapid-eye-movement sleep (REMS), compared to EU. Similarly, CDKL5-KO mice had an augmented occurrence rate of OSA during REMS, whereas no differences were observed for CSA, compared to CDKL5-WT. Preliminary data on BMP7-KO mice indicated an increased occurrence rate of CSA during NREMS, as well as of both CSA and OSA during REMS, compared to BMP7-WT mice. Conclusions. Mice exhibited varying degrees of airway obstruction like humans. Therefore, TS and CDKL5-KO mice, recapitulating DS and CDD, are valid models of OSA, whereas BMP7-KO mice, mimicking PRS, require further investigation.