AUTHOR=Vogelgesang Steffen , Niebert Marcus , Bischoff Anne M. , Hülsmann Swen , Manzke Till TITLE=Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice JOURNAL=Frontiers in Molecular Neuroscience VOLUME=11 YEAR=2018 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2018.00028 DOI=10.3389/fnmol.2018.00028 ISSN=1662-5099 ABSTRACT=

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_5b (Htr5b) in the brainstem. To investigate whether the persistence of 5-ht_5b expression is contributing to the respiratory phenotype, we crossbred MeCP2-deficient mice with 5-ht_5b-deficient mice to generate double knockout mice (Mecp2^−/y;Htr5b^−/−). To compare respiration between wild type (WT), Mecp2^−/y and Mecp2^−/y;Htr5b^−/− mice, we used unrestrained whole-body plethysmography. While the breathing of MeCP2-deficient male mice (Mecp2^−/y) 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_5b 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_5b receptors to G_i proteins is altering second messenger signaling. Tissue cAMP levels in the medulla of Mecp2^−/y mice were decreased as compared to WT mice. In contrast, cAMP levels in Mecp2^−/y;Htr5b^−/− mice were indistinguishable from WT mice. Taken together, our data points towards a role of 5-ht_5b receptors within the complex breathing phenotype of MeCP2-deficient mice.