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

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 (<i>Htr5b</i>) 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 (<i>Mecp2^-/y</i> ;<i>Htr5b</i>^-/-). To compare respiration between wild type (WT), <i>Mecp2^-/y</i> and <i>Mecp2^-/y</i> ;<i>Htr5b</i>^-/- mice, we used unrestrained whole-body plethysmography. While the breathing of MeCP2-deficient male mice (<i>Mecp2^-/y</i> ) 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 <i>Mecp2^-/y</i> mice were decreased as compared to WT mice. In contrast, cAMP levels in <i>Mecp2^-/y</i> ;<i>Htr5b</i>^-/- 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.