Modulating GABAA receptors that contain alpha 2/3 subunits corrects respiratory disturbances in a mouse model of Rett syndrome

Abstract

We have recently shown that augmenting γ‐aminobutyric acid (GABA) A inhibition in a mouse model of Rett syndrome corrects periodic apneas and restores cycle regularity to that of wild type (2008 EB abstracts [on CD‐ROM], Abstract#1232.12). These mice are deficient in α2 subunits of GABAA receptors (J Neurophysiol 99:112, 2008). Here we show that allosteric modulation of GABAA receptors with a compound that is relatively specific for receptors that contain α2/3 subunits (L‐838,417, Nature Neurosci 3:587, 2000) is equally efficient as a broad‐spectrum benzodiazepine in correcting the respiratory disorder. Studies were performed in heterozygous methyl‐CpG‐binding protein 2 (Mecp2) deficient female mice with continuous monitoring of pleural pressure by telemetry. Following ip injection of L‐838,417 (20 mg/Kg) or vehicle respiratory pattern was examined for 3 hrs.Adjusting for differences in wake/sleep pattern from animal activity (Physiol Genomics 28:232, 2006) did not alter the effect of L‐838,417.Support: MOD #6‐FY‐314 and IRSF #0802