The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome

syndrome (RTT) have breathing instability in addition to other neu-ropathological manifestations. The breathing disturbances contribute to the high incidence of unexplained death and abnormal brain development. However, the cellular mechanisms underlying the breathing abnormalities remain unclear. To test the hypothesis that the central CO2 chemoreception in these people is disrupted, we studied the CO2 chemosensitivity in a mouse model of RTT. The Mecp2-null mice showed a selective loss of their respiratory response to 1–3 % CO2 (mild hypercapnia), whereas they displayed more regular breathing in response to 6 –9 % CO2 (severe hypercapnia). The defect was alleviated with the NE uptake blocker desipramine (10 mg·kg1·day1 ip, for 5–7 days). Consistent with the in vivo observations, in vitro studies in brain slices indicated that CO2 chemosensitivity of locus coeruleus (LC) neurons was impaired in Mecp2-null mice. Two major neuronal pH-sensitive Kir currents tha