Mecp2 Deficiency Disrupts Norepinephrine and Respiratory Systems in Mice

Abstract

Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We usedin vivoplethysmography,in vitroelectrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of theMECP2mutation on breathing in wild-type (wt) andMecp2-deficient (Mecp2-/y) mice. At birth,Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At ∼1 month of age, mostMecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even inMecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetizedMecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at ∼2 months of age. During their last week of life,Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content.In vitroexperiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular inMecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances inMecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.