Breathing and Oxygen Carrying Capacity in Ts65Dn and Down Syndrome

Abstract

Individuals with Down Syndrome are at increased risk of respiratory infection, aspiration pneumonia, and apnea. The Ts65Dn mouse is a commonly used model of Ds, but there have been no formal investigations of awake breathing and respiratory muscle function in these mice. We hypothesized that breathing would be impaired in Ts65Dn vs. wild-type (WT), and would be mediated by both neural and muscular inputs. Baseline minute ventilation with room air was not different at 3, 6 or 12 months of age. However, VT/Ti, a marker of the neural drive to breathe, was lower in Ts65Dn vs. WT. Central apneas were more prevalent in Ts65Dn compared to WT. The response to breathing hypoxia was not different, but the response to hypercapnia was attenuated in Ts65Dn at 3 and 12 months, revealing a difference in carbon dioxide sensing, and/or motor output. Oxygen desaturations were present in room air, demonstrating that ventilation may not be sufficient to maintain adequate oxygen saturation in Ts65Dn. We observed no differences in arterial PO2 or PCO2, but Ts65Dn mice had lower hemoglobin and hematocrit. A retrospective medical record review of 52 346 Ds and 52 346 controls confirmed an elevated relative risk of anemia in Ds individuals. To determine the muscular contribution to respiratory impairment, we performed eupneic in vivo electromyography and in vitro muscle function and histological fiber typing of the diaphragm, and found no difference between strains. Overall, conscious respiration is impaired in Ts65Dn mice, is mediated by neural mechanisms, and results in reduced hemoglobin saturation. Oxygen carrying capacity is reduced in Ts65Dn vs. WT, and we demonstrate that individuals with Ds are also at increased risk of anemia.

Carbonyl Reductase 1: a novel regulator of blood pressure in Down Syndrome

“…These animals have been well characterised with regards cerebellar volume which is reduced, as in DS 29 . They demonstrate increased locomotor activity and energy expenditure 32 (33), have reduced blood pressure 33 and impaired conscious respiration associated with a decreased neural drive 34 . Mice heterozygous for Cbr1 (Cbr1 +/- ) were generated as previously described 28 , homozygosity of this gene deletion is foetal lethal 35 .…”