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Persistent Expression of Serotonin Receptor 5b Alters Breathing Behavior in Male MeCP2 Knockout Mice
Steffen Vogelgesang1,2, Marcus Niebert1,2, Anne M Bischoff1,3
1DFG-Research Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University of Göttingen, Göttingen, Germany.
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 ;Htr5b-/-). To compare respiration between wild type (WT), Mecp2 and Mecp2 ;Htr5b-/- mice, we used unrestrained whole-body plethysmography. While the breathing of MeCP2-deficient male mice (Mecp2 ) 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 mice were decreased as compared to WT mice. In contrast, cAMP levels in Mecp2 ;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.
Insights
Mecp2 mutations cause Rett syndrome and breathing issues. Removing the 5-ht5b receptor in Mecp2-deficient mice normalized breathing patterns and cAMP levels, suggesting its role in the respiratory phenotype.
Area of Science:
- Neuroscience
- Genetics
- Respiratory Physiology
Background:
- Mutations in methyl-CpG-binding protein 2 (MeCP2) lead to Rett syndrome (RTT), a neurodevelopmental disorder.
- RTT patients and MeCP2-deficient mice exhibit irregular breathing patterns, including apneas.
- Persistent expression of the serotonin receptor 5-ht5b (Htr5b) in the brainstem of MeCP2-deficient mice is linked to this phenotype.
Purpose of the Study:
- To investigate the contribution of persistent 5-ht5b receptor expression to the respiratory abnormalities in MeCP2-deficient mice.
- To determine if eliminating 5-ht5b receptor function can ameliorate the breathing deficits associated with MeCP2 deficiency.
Main Methods:
- Generation of double knockout mice (Mecp2 ;Htr5b-/-) by crossbreeding MeCP2-deficient and 5-ht5b-deficient mice.
- Unrestrained whole-body plethysmography to compare respiratory parameters (breathing rate, pauses) between wild type (WT), Mecp2-/-, and Mecp2 ;Htr5b-/- mice.
- Measurement of tissue cyclic adenosine monophosphate (cAMP) levels in the medulla to assess second messenger signaling.
Main Results:
- MeCP2-deficient mice (Mecp2-/-) displayed slow breathing rates and prolonged respiratory pauses.
- In double knockout mice (Mecp2 ;Htr5b-/-), breathing rate and the number of pauses were normalized, becoming indistinguishable from WT mice.
- Medulla cAMP levels were decreased in Mecp2-/- mice but normalized in Mecp2 ;Htr5b-/- mice compared to WT.
Conclusions:
- The 5-ht5b receptor plays a significant role in the complex respiratory phenotype observed in MeCP2-deficient mice.
- Eliminating 5-ht5b receptor expression rescues the abnormal breathing patterns and restores normal cAMP signaling in the medulla.
- Targeting 5-ht5b receptor pathways may offer therapeutic potential for respiratory dysfunctions in Rett syndrome.
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