Supporting information for: Mecp2 deficiency induces dysphagia in a preclinical model of Rett Syndrome

Rett Syndrome is an x-linked genetic neurological disorder primarily caused by mutations in the MECP2 gene. This progressive neurodevelopmental condition hinders patients’ ability to breathe and eat normally. It remains unclear how Mecp2-deficiency leads to the high prevalence of dysphagia and aspiration pneumonia observed in individuals with Rett syndrome. This study aims to determine the effects of Mecp2-deficiency on swallow-related neuromuscular mechanisms that contribute to dysphagia in Rett syndrome. Swallow-related submental complex duration and amplitude were significantly decreased in both Mecp2-/y and Mecp2+/- mice compared to wild-type, likely due to reduced motor unit activation. In Mecp2-deficient mice, cholinergic immunoreactivity in the hypoglossal, facial, and trigeminal motor nuclei was decreased in post-symptomatic, but not presymptomatic mice. We also observed a significant increase in the transition time from inspiration to swallow, swallow to the subsequent inspiration, and impaired post-swallow respiratory rhythm resumption in Mecp2-/y, but not Mecp2+/- mice. The combination of decreased ChAT+ cells in brainstem motor nuclei and reduced submental muscle complex activity suggest impaired swallow-related hyolaryngeal elevation and laryngeal vestibular closure. These results provide insight into a neuromuscular mechanism underlying dysphagia in Rett syndrome and support the use of Mecp2-deficient mice as a viable preclinical model for further investigation of swallow and upper airway dysfunction in Rett syndrome.