Insufficient GABA inhibition underlies periodic and irregular breathing in methyl‐CpG‐binding protein 2 (Mecp2) deficient mice

Abstract

Mutations in the MECP2 gene cause Rett syndrome (RTT) whose phenotype includes periodic (PB) and irregular breathing. Using telemetry to record pleural pressure we have found that heterozygous Mecp2 deficient female mice have frequent episodes of PB. The amount of PB was augmented by breathing 40 % oxygen and decreased in 12% oxygen, indicating that peripheral chemoreception is not responsible for the increased controller gain (J Appl Physiol in Press). Medullary respiratory neurons (Brain Research 710:150,1996; J Neurophysiol 80:2368,1998) and phrenic motoneuons (J Neurosci 19:2368,1999) receive concurrent inhibition with excitation during inspiration. Mecp2+/− are relatively deficient in the β3 subunit of GABAA receptors (Hum Mol Genet 14:483,2005). We hypothesized that insufficient GABA inhibition underlies the increased controller gain in Mecp2 deficient animals. NO‐711 a GABA transport inhibitor reduced the number of PB episodes from 18.1±4.9 to 3.5±1.8/hr. and extended the longest period without PB from 26.5±6 to 74.5±23.7 min. Similarly the GABA receptor modulator diazepam reduced the incidence to 3.2±0.7/hr and extended PB free to 96.7±35.9 min. NO‐711 reduced the coefficient of variation for TTOT from 35±3.4 to 22.6±3.8%. These data indicate that augmenting GABA reduces PB and respiratory irregularity seen in Mecp2 deficient mice to the levels observed in wild type mice. MOD 6‐FY06‐314