Separate respiratory phenotypes in methyl-CpG-binding protein 2 (Mecp2) deficient mice

Area of Science:

• Neuroscience
• Genetics
• Respiratory Physiology

Background:

• Rett syndrome (RTT) is a neurodevelopmental disorder linked to MECP2 gene mutations.
• RTT patients exhibit respiratory abnormalities, including depression after hyperventilation.
• Previous studies suggested neuronal deficiency causes RTT symptoms.

Purpose of the Study:

• To investigate the role of organ distribution of MECP2 deficiency in RTT-related respiratory phenotype.
• To determine if neuronal MECP2 deficiency alone causes respiratory depression in RTT models.

Main Methods:

• Comparison of respiratory responses to hypoxia and hypercapnia in different mouse models of MECP2 deficiency.
• Mice models included heterozygous null mutation (Mecp2+/-) and neuron-specific deletion (Mecp2+/nestin-Cre lox).
• Measurements included tidal volume, lung volume, and respiratory depression following hypoxic hyperventilation.

Main Results:

• Both Mecp2+/- and Mecp2+/nestin-Cre lox mice showed initial exaggerated responses to hypoxia compared to wild type.
• Marked respiratory depression after hypoxic hyperventilation was observed only in Mecp2+/- mice.
• Adding carbon dioxide abolished respiratory depression, and depression correlated with increased tidal volume, suggesting hypocapnia.

Conclusions:

• Respiratory depression in this RTT mouse model is dependent on the extent of MECP2 deficiency.
• Ubiquitous MECP2 deficiency, not solely neuronal deficiency, underlies the observed respiratory depression.
• Hypocapnia resulting from increased tidal volume is the likely cause of respiratory depression in RTT models with widespread MECP2 deficiency.