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-ht5b (Htr5b) in the brainstem. To investigate whether the persistence of 5-ht5b expression is contributing to the respiratory phenotype, we crossbred MeCP2-deficient mice with 5-ht5b-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-ht5b 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-ht5b receptors to Gi 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-ht5b receptors within the complex breathing phenotype of MeCP2-deficient mice.

Whole-body plethysmography revisited

“…In summary, undoubtedly UWBP allows to determine parameters of respiratory rhythm, respiratory rate as well as parameters that define regularity of the respiratory rhythm an also phases of respiratory arrest (Hulsmann et al ., 2016; Vogelgesang et al ., 2017; Mesuret et al ., 2018; Vogelgesang et al ., 2018). However, for defining tidal volume, UWBP is a weak method.…”

Overexpression of serotonin receptor 5b expression rescues neuronal and behavioral deficits in a mouse model of Kabuki syndrome

“…In addition, selective agonist or antagonist are still no available for 5-HT 5B . Therefore, up to now, a very limited number of studies were conducted to address the function of 5-ht 5b in CNS ( Maekawa et al, 2010 ; Vogelgesang et al, 2017 , 2018 ; Niebert et al, 2017 ).…”

“…However, there are only two studies that report the possible roles of 5-ht 5b in the regulation of animal behavior. 5-HT5B has been found to be dramatically upregulated in mice undergoing social stress ( Maekawa et al, 2010 ) and in mouse models of Rett syndrome (RTT) ( Vogelgesang et al, 2018 ; Niebert et al, 2017 ), a severe neurodevelopmental disorder caused by mutations in the transcription factor MeCP2. The role of 5-HT5B in the brain remains to be determined.…”

“…Previous study suggests that upregulation of 5-ht 5b in the dorsal raphe nuclei might partly contribute to the abnormal behaviors of Atf7 deficient or social isolation stress mice ( Maekawa et al, 2010 ). Recently, in Mecp2 deficient mice, a mouse model of Rett syndrome (RS), 5-HT5B dysregulation is a key but probably not the only factor that mediates irregular breathing behavior ( Vogelgesang et al, 2017 , 2018 ).…”

Sleep disordered breathing and daytime hypoventilation in a male with MECP2 mutation

“…Ure et al also demonstrated that restoration of MECP2 gene in GABAergic neurons in RTT mouse models caused the improvement of multiple RTT‐like phenotypes: respiratory anomalies however were not included, suggesting an interplay of multiple factors at the basis of normal respiration (Ure et al, 2016). It is not fully understood which are the causes related to abnormal breathing in RTT, but studies suggest the involvement of norepinephrine (Viemari et al, 2005), neurotrophic factors like BDNF (Li & Pozzo‐Miller, 2014), dysregulation of expression of 5‐ht5b‐receptors (Vogelgesang, Niebert, Bischoff, Hülsmann, & Manzke, 2018) or decrease in excitatory synaptic connectivity in several parts of brain cortex, including the medial prefrontal cortex (Sceniak et al, 2016). Studies on MECP2 ‐null mice show also an altered sensitivity to blood gases: increased hypoxia susceptibility associated with failure to increase ventilation in presence of moderate hypercapnia (Jiang, Cui, Zhong, Johnson, & Wu, 2017).…”