Abstract
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.
Highlights
Rett syndrome (RTT, OMIM 312750) is a neurodevelopment disorder caused by mutations in the X-linked gene MethylCpG Binding Protein 2 (MECP2) that is characterized by initial normal development followed by regression manifesting as loss of acquired skills [1,2,3]
We identified that mice lacking Methyl-CpG-Binding Protein 2 (MeCP2) acquire a deficit in hypoxic ventilatory decline (HVD), presenting with a persistently increased breathing rate during exposure to hypoxia
Genetic knockout and rescue of Mecp2 within glutamatergic, GABAergic, and dopaminergic/noradrenergic neurons indicates that MeCP2 function is required in a distributed set of neurons for a normal breathing response to hypoxia
Summary
Rett syndrome (RTT, OMIM 312750) is a neurodevelopment disorder caused by mutations in the X-linked gene MethylCpG Binding Protein 2 (MECP2) that is characterized by initial normal development followed by regression manifesting as loss of acquired skills [1,2,3]. The abnormal breathing pattern may indicate deficits in the networks that maintain normal respiratory rhythmogenesis as well as those that modify its response to environmental stimuli [7]. While female mice heterozygous for Mecp mutations show many features reminiscent of the human disorder, the nature of the X-linked mutation causes them to be mosaic for MeCP2 and less severely affected than hemizygous male animals. For these reasons, male mice are often used to help dissect anatomic and neuronal population effects of MeCP2 expression. The increase in ventilation followed by ventilatory decline until ventilation approaches baseline levels is commonly referred to as the hypoxic ventilatory response, with the ventilatory decline stage often referred to as hypoxic ventilatory decline (HVD) [16, 20, 21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
