Mecp2 deficiency induces dysphagia in a preclinical model of Rett syndrome.

Abstract

Rett syndrome is an x-linked genetic neurological disorder primarily caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. This progressive neurodevelopmental condition hinders patients' ability to breathe and eat normally. It remains unclear how <i>Mecp2</i> 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 <i>Mecp2</i> 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 <i>Mecp2</i>^-/y and <i>Mecp2</i>^+/- mice compared to wild-type, likely due to reduced motor unit activation. In <i>Mecp2-</i>deficient mice, cholinergic immunoreactivity in the hypoglossal, facial, and trigeminal motor nuclei was decreased in postsymptomatic, 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 <i>Mecp2</i>^-/y, but not <i>Mecp2</i>^+/- 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 <i>Mecp2-</i>deficient mice as a viable preclinical model for further investigation of swallow and upper airway dysfunction in Rett syndrome.