Carotid body dysfunction contributes to respiratory instability in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2. Disordered breathing is a hallmark feature of RTT that negatively impacts quality of life and can be life-threatening. Despite this, the mechanisms underlying disordered breathing in RTT are poorly understood. Although RTT is primarily considered a central nervous system disorder, we found that increased drive from peripheral respiratory chemoreceptors may contribute to unstable breathing in MeCP2-deficient mice. Consistent with this, breathing pure oxygen to limit the output of peripheral chemoreceptors stabilized breathing in MeCP2-deficient mice. Also, knockdown of MeCP2 within the carotid body recapitulates RTT-like unstable breathing. We also found that MeCP2 deficiency alters the carotid body transcriptome, including the disruption of genes involved in dopaminergic signaling, and treatment with a dopamine receptor agonist stabilized breathing in MeCP2-deficient mice. These results identify the peripheral chemoreceptors as high-priority therapeutic targets for disordered breathing in RTT.