Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice.

Mutations in the transcription factor methyl-CpG-binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome (RTT). Besides many other neurological problems, RTT patients show irregular breathing with recurrent apneas or breath-holdings. MeCP2-deficient mice, which recapitulate this breathing phenotype, show a dysregulated, persistent expression of G-protein-coupled serotonin receptor 5-ht () in the brainstem. To investigate whether the persistence of 5-ht expression is contributing to the respiratory phenotype, we crossbred MeCP2-deficient mice with 5-ht-deficient mice to generate double knockout mice ( ;). To compare respiration between wild type (WT), and ; mice, we used unrestrained whole-body plethysmography. While the breathing of MeCP2-deficient male mice ( ) at postnatal day 40 is characterized by a slow breathing rate and the occurrence of prolonged respiratory pauses, we found that in MeCP2-deficient mice, which also lacked the 5-ht receptor, the breathing rate and the number of pauses were indistinguishable from WT mice. To test for a potential mechanism, we also analyzed if the known coupling of 5-ht receptors to G proteins is altering second messenger signaling. Tissue cAMP levels in the medulla of mice were decreased as compared to WT mice. In contrast, cAMP levels in ; mice were indistinguishable from WT mice. Taken together, our data points towards a role of 5-ht receptors within the complex breathing phenotype of MeCP2-deficient mice.