Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder

Abstract

A characteristic feature of Rett syndrome (RTT) is abnormal breathing accompanied by several other neurological and cognitive disorders. Since RTT rodent models became available, studies have begun shedding insight into the breathing abnormalities at behavioral, cellular and molecular levels. Defects are found in several groups of brainstem neurons involved in respiratory control, and potential neural mechanisms have been suggested. The findings in animal models are helpful in therapeutic strategies for people with RTT with respect to lowering sudden and unexpected death, preventing secondary developmental consequences, and improving the quality of lives.

Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett Syndrome Mice

“…Therefore, 4-6 week-old male RTT mice were used for all experiments. Female, heterozygous Mecp2 Bird/+ mice (female RTT mice) display respiratory problems at 6 months of age or older (Jiang et al, 2017). Therefore, 6-10 month-old adult female mice were used for all experiments.…”

“…Respiratory disturbances are very severe in male RTT mice that completely lack Mecp2 protein (Katz et al, 2009; Voituron et al, 2009). Female RTT mice also have breathing problems that arise developmentally later compared to males, likely due to mosaic expression of functional Mecp2 protein as a result of partial X -inactivation (Abdala et al, 2010; Bissonnette & Knopp, 2008; Jiang et al, 2017; Levitt et al, 2013; Samaco et al, 2013). Male and female RTT mice are useful models for uncovering dysfunction within the brainstem respiratory control network that underlies breathing irregularity in RTT.…”

Hypoventilation and sleep hypercapnia in a case of congenital variant-like Rett syndrome

“…MECP2 gene plays an important role in autonomic system regulation and its mutations are causative of Rett syndrome [15]. Animal models showed the importance of MECP2 for a correct sensitivity to CO2 of breathing centres, and its mutations may lead to the typical respiratory instability of RS [16], and possibly to hypoventilation as proved by animal models [17]. To the best of our knowledge, this is the first case reporting hypoxemia and persistent hypercapnia during sleep-time in a patient affected by a congenital form of RS.…”

“…Of particular interest is the persistent periodic breathing of this patient. Breathing centres homeostasis is very fragile in RS due to MECP2 mutation [16], with a consequent high gain loop causing periodic breathing. Such events may be boosted by repeated desaturations caused by CRS-related hypotonia [12,13].…”

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

“…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). The clinical spectrum of disorders, particularly of breathing behavior, related to MECP2 mutations in males is not fully understood.…”