Rett Syndrome mutation MeCP2 T158A affects hypoxic ventilatory response in mice

Abstract

Rett syndrome (RTT), whose phenotype includes respiratory disorders, is caused by loss‐of‐function mutations in methyl‐CpG‐binding protein 2 (MeCP2). Mouse models of the syndrome that have been generated by deletion of Mecp2 have an altered ventilatory response to acute hypoxia (HVR) characterized by a minute ventilation (VE) that exceeds wild type (WT) and that persists in the early recovery period. Such large deletions, however, account for only ~10% of cases. Here we determine if mice with a common single point mutation retain this respiratory pattern. Knockin mice that carry a RTT‐associated threonine to alanine mutation at residue 158 (T158A) show RTT‐like behavioral phenotypes similar to Mecp2‐null mice (Nature Neuroscience 15:274,2011). Experiments were performed in heterozygous T158A female mice at 9 months of age. Baseline respiratory frequency, tidal volume and minute ventilation in T158A animals was similar to WT. Compared to WT littermates relative VE of T158A at 1 min of 8% O2 was twice as large. WT mice showed the expected post‐hypoxia frequency decline (224±9.5 to 203±12 bpm) while T158A had a sustained tachypnea (203±10 to 219±14.5). HVR in mice with a T158A mutation is similar to that with a null mutation of MeCP2.Support: IRSF, RSRT, NewLife Foundation (JMB); NIH, IRSF (ZZ)