Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia
Rett Syndrome (RTT) is a neurodevelopmental disorder caused by loss of function of the transcriptional regulator Methyl-CpG-Binding Protein 2 (MeCP2). In addition to the characteristic loss of hand function and spoken language after the first year of life, people with RTT also have a variety of phys...
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2020.593554/full |
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| author | Christopher S. Ward Christopher S. Ward Christopher S. Ward Teng-Wei Huang Teng-Wei Huang Jose A. Herrera Jose A. Herrera Rodney C. Samaco Rodney C. Samaco Christopher M. McGraw Christopher M. McGraw Diana E. Parra E. Melissa Arvide Aya Ito-Ishida Aya Ito-Ishida Xiangling Meng Xiangling Meng Kerstin Ure Kerstin Ure Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul |
| author_facet | Christopher S. Ward Christopher S. Ward Christopher S. Ward Teng-Wei Huang Teng-Wei Huang Jose A. Herrera Jose A. Herrera Rodney C. Samaco Rodney C. Samaco Christopher M. McGraw Christopher M. McGraw Diana E. Parra E. Melissa Arvide Aya Ito-Ishida Aya Ito-Ishida Xiangling Meng Xiangling Meng Kerstin Ure Kerstin Ure Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul |
| author_sort | Christopher S. Ward |
| collection | DOAJ |
| description | Rett Syndrome (RTT) is a neurodevelopmental disorder caused by loss of function of the transcriptional regulator Methyl-CpG-Binding Protein 2 (MeCP2). In addition to the characteristic loss of hand function and spoken language after the first year of life, people with RTT also have a variety of physiological and autonomic abnormalities including disrupted breathing rhythms characterized by bouts of hyperventilation and an increased frequency of apnea. These breathing abnormalities, that likely involve alterations in both the circuitry underlying respiratory pace making and those underlying breathing response to environmental stimuli, may underlie the sudden unexpected death seen in a significant fraction of people with RTT. In fact, mice lacking MeCP2 function exhibit abnormal breathing rate response to acute hypoxia and maintain a persistently elevated breathing rate rather than showing typical hypoxic ventilatory decline that can be observed among their wild-type littermates. Using genetic and pharmacological tools to better understand the course of this abnormal hypoxic breathing rate response and the neurons driving it, we learned that the abnormal hypoxic breathing response is acquired as the animals mature, and that MeCP2 function is required within excitatory, inhibitory, and modulatory populations for a normal hypoxic breathing rate response. Furthermore, mice lacking MeCP2 exhibit decreased hypoxia-induced neuronal activity within the nucleus tractus solitarius of the dorsal medulla. Overall, these data provide insight into the neurons driving the circuit dysfunction that leads to breathing abnormalities upon loss of MeCP2. The discovery that combined dysfunction across multiple neuronal populations contributes to breathing dysfunction may provide insight into sudden unexpected death in RTT. |
| first_indexed | 2024-12-11T13:37:41Z |
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| institution | Directory Open Access Journal |
| issn | 1664-2295 |
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| last_indexed | 2024-12-11T13:37:41Z |
| publishDate | 2020-10-01 |
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| series | Frontiers in Neurology |
| spelling | doaj.art-068530e644a94a5095446b5ab905b4e52022-12-22T01:04:57ZengFrontiers Media S.A.Frontiers in Neurology1664-22952020-10-011110.3389/fneur.2020.593554593554Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute HypoxiaChristopher S. Ward0Christopher S. Ward1Christopher S. Ward2Teng-Wei Huang3Teng-Wei Huang4Jose A. Herrera5Jose A. Herrera6Rodney C. Samaco7Rodney C. Samaco8Christopher M. McGraw9Christopher M. McGraw10Diana E. Parra11E. Melissa Arvide12Aya Ito-Ishida13Aya Ito-Ishida14Xiangling Meng15Xiangling Meng16Kerstin Ure17Kerstin Ure18Huda Y. Zoghbi19Huda Y. Zoghbi20Huda Y. Zoghbi21Huda Y. Zoghbi22Huda Y. Zoghbi23Huda Y. Zoghbi24Huda Y. Zoghbi25Jeffrey L. Neul26Jeffrey L. Neul27Jeffrey L. Neul28Jeffrey L. Neul29Jeffrey L. Neul30Jeffrey L. Neul31Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesProgram in Developmental Biology, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesInterdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesProgram in Developmental Biology, Baylor College of Medicine, Houston, TX, United StatesDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, United StatesDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Neuroscience, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesProgram in Developmental Biology, Baylor College of Medicine, Houston, TX, United StatesInterdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, United StatesDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, United StatesDepartment of Neuroscience, Baylor College of Medicine, Houston, TX, United StatesHoward Hughes Medical Institute, Baylor College of Medicine, Houston, TX, United StatesJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, United StatesDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesProgram in Developmental Biology, Baylor College of Medicine, Houston, TX, United StatesInterdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, United StatesDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, United StatesDepartment of Neuroscience, Baylor College of Medicine, Houston, TX, United StatesRett Syndrome (RTT) is a neurodevelopmental disorder caused by loss of function of the transcriptional regulator Methyl-CpG-Binding Protein 2 (MeCP2). In addition to the characteristic loss of hand function and spoken language after the first year of life, people with RTT also have a variety of physiological and autonomic abnormalities including disrupted breathing rhythms characterized by bouts of hyperventilation and an increased frequency of apnea. These breathing abnormalities, that likely involve alterations in both the circuitry underlying respiratory pace making and those underlying breathing response to environmental stimuli, may underlie the sudden unexpected death seen in a significant fraction of people with RTT. In fact, mice lacking MeCP2 function exhibit abnormal breathing rate response to acute hypoxia and maintain a persistently elevated breathing rate rather than showing typical hypoxic ventilatory decline that can be observed among their wild-type littermates. Using genetic and pharmacological tools to better understand the course of this abnormal hypoxic breathing rate response and the neurons driving it, we learned that the abnormal hypoxic breathing response is acquired as the animals mature, and that MeCP2 function is required within excitatory, inhibitory, and modulatory populations for a normal hypoxic breathing rate response. Furthermore, mice lacking MeCP2 exhibit decreased hypoxia-induced neuronal activity within the nucleus tractus solitarius of the dorsal medulla. Overall, these data provide insight into the neurons driving the circuit dysfunction that leads to breathing abnormalities upon loss of MeCP2. The discovery that combined dysfunction across multiple neuronal populations contributes to breathing dysfunction may provide insight into sudden unexpected death in RTT.https://www.frontiersin.org/articles/10.3389/fneur.2020.593554/fullRettMeCP2hypoxiasudden deathbiomarkerbreathing abnormalities |
| spellingShingle | Christopher S. Ward Christopher S. Ward Christopher S. Ward Teng-Wei Huang Teng-Wei Huang Jose A. Herrera Jose A. Herrera Rodney C. Samaco Rodney C. Samaco Christopher M. McGraw Christopher M. McGraw Diana E. Parra E. Melissa Arvide Aya Ito-Ishida Aya Ito-Ishida Xiangling Meng Xiangling Meng Kerstin Ure Kerstin Ure Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Huda Y. Zoghbi Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Jeffrey L. Neul Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia Frontiers in Neurology Rett MeCP2 hypoxia sudden death biomarker breathing abnormalities |
| title | Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia |
| title_full | Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia |
| title_fullStr | Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia |
| title_full_unstemmed | Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia |
| title_short | Loss of MeCP2 Function Across Several Neuronal Populations Impairs Breathing Response to Acute Hypoxia |
| title_sort | loss of mecp2 function across several neuronal populations impairs breathing response to acute hypoxia |
| topic | Rett MeCP2 hypoxia sudden death biomarker breathing abnormalities |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2020.593554/full |
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