Noninvasive assessment of autonomic modulation of heart rate variability in the Ts65Dn mouse model of Down syndrome: A proof of principle study

Introduction: The Ts65Dn mouse is the most widely used animal model of Down syndrome (DS). Differences in autonomic regulation of heart rate variability (HRV) in individuals with DS have been hypothesized. Pharmacological studies in animal models may help us understand mechanisms underlying observed changes in HRV in people with DS. Objective: To investigate the use a new, noninvasive technique to assess cardiac autonomic modulation in Ts65Dn mice under the effect of adrenergic and cholinergic agonists. Method: We recorded electrocardiograms (ECGs) from 12 Ts65Dn and 12 euploid control mice. A 30-min baseline recording was followed by the injection of an adrenergic (isoproterenol [Iso]) or cholinergic (carbachol [CCh]) agonist. Heart rate and HRV were analyzed using a series of methods customized for mice. Results and Discussion: The ECG apparatus described here allowed us to detect noninvasively long series of heartbeats in freely-moving animals. During baseline conditions, the yield of detectable heartbeats was 3%-27% of the estimated total number of events, which increased to 35%-70% during the 15-min period after either Iso or CCh injections. Ts65Dn mice displayed a robust enhanced Iso-induced negative chronotropic rebound response compared with euploid control mice. We observed a significantly smaller CCh response in Ts65Dn versus control euploid mice in the 6- to 10-min-interval postcarbachol injection. Conclusion: This work showed that the techniques described here are sufficient for this type of study. However, future studies involving the use of more selective pharmacological agents and/or genetic manipulations will be key to advance a mechanistic understanding of cardiac autonomic regulation in DS.