Pediatr Res. 2006 Apr;59(4):513-8.
Separate Respiratory Phenotypes in Methyl-CpG-Binding Protein 2 (Mecp2) Deficient Mice
Bissonnette JM, Knopp SJ.
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) that encodes a DNA binding protein involved in gene silencing. Selective deletion of Mecp2 in post-mitotic neurons in mice results in a Rett-like phenotype characterized by disturbances in motor activity and body weight, suggesting that these symptoms are exclusively caused by neuronal deficiency. Included in the RTT phenotype are episodes of respiratory depression that follow hyperventilation. Here we show that the respiratory phenotype depends on the organ distribution of Mecp2 deficiency. Both female mice heterozygous for a null mutation in Mecp2 (Mecp2(+/-)) and those with selective deletion of the protein in neurons (Mecp2(+/nestin-Cre lox)), showed an initial response to hypoxia that exceeded that in wild type (WT). However, marked respiratory depression following hypoxic hyperventilation was only seen in Mecp2(+/-) animals. Addition of carbon dioxide to the hypoxic exposure eliminated the respiratory depression. Tidal volume and lung volume were larger in Mecp2(+/-) and respiratory depression was directly related to tidal volume. Taken together these results indicate that the depression is due to hypocapnia. Respiratory depression in this mouse model of Rett Syndrome is seen in with ubiquitous deficiency in Mecp2 but not when it is confined to neurons.
Lay Summary
Breathing irregularities observed in Rett syndrome may include episodes of apnea (breath holding) and hyperventilation. In this study, the investigators examine several mouse models of Rett syndrome to better understand the mechanisms underlying this altered breathing behaviour. Interesting, the mouse breathing behaviour which best mimics that of Rett syndrome was observed in those mice which lack MeCP2 throughout the whole body, rather than in those mice which lack MeCP2 expression only in the brain. This is an important finding, as it suggests that MeCP2 mutations external to the brain probably play a significant role in the development of breathing disorders in Rett syndrome patients. Furthermore, it was shown that respiratory depression following hyperventilation - a common occurrence in Rett patients - is causes by hypocapnia. Hypocapnia is a state in which the level of carbon dioxide in the blood is lower than normal, and is a product of the hyperventilation. Although hypocapnia is normally well tolerated, it can cause constriction of brain blood flow, often leading to lack of brain oxygen and thus temporary dizziness, visual disturbances, and anxiety.