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

Am J Physiol Cell Physiol. 2011 Sep;301(3):C729-38. doi: 10.1152/ajpcell.00334.2010. Epub 2011 Feb 9.


People with Rett syndrome (RTT) have breathing instability in addition to other neuropathological 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 CO(2) chemoreception in these people is disrupted, we studied the CO(2) chemosensitivity in a mouse model of RTT. The Mecp2-null mice showed a selective loss of their respiratory response to 1-3% CO(2) (mild hypercapnia), whereas they displayed more regular breathing in response to 6-9% CO(2) (severe hypercapnia). The defect was alleviated with the NE uptake blocker desipramine (10 mg·kg(-1)·day(-1) ip, for 5-7 days). Consistent with the in vivo observations, in vitro studies in brain slices indicated that CO(2) chemosensitivity of locus coeruleus (LC) neurons was impaired in Mecp2-null mice. Two major neuronal pH-sensitive Kir currents that resembled homomeric Kir4.1 and heteromeric Ki4.1/Kir5.1 channels were identified in the LC neurons. The screening of Kir channels with real-time PCR indicated the overexpression of Kir4.1 in the LC region of Mecp2-null mice. In a heterologous expression system, an overexpression of Kir4.1 resulted in a reduction in the pH sensitivity of the heteromeric Kir4.1-Kir5.1 channels. Given that Kir4.1 and Kir5.1 subunits are also expressed in brain stem respiration-related areas, the Kir4.1 overexpression may not allow CO(2) to be detected until hypercapnia becomes severe, leading to periodical hyper- and hypoventilation in Mecp2-null mice and, perhaps, in people with RTT as well.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Carbon Dioxide / metabolism*
  • Carbon Dioxide / pharmacology
  • Chemoreceptor Cells / drug effects
  • Chemoreceptor Cells / physiology*
  • Desipramine / pharmacology
  • Desipramine / therapeutic use
  • Disease Models, Animal
  • Electric Impedance
  • Electrophysiological Phenomena / drug effects
  • Electrophysiological Phenomena / physiology
  • Female
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Hypercapnia / physiopathology
  • Locus Coeruleus / cytology
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / physiopathology
  • Lung / physiopathology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Norepinephrine / metabolism
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Rats
  • Respiration / drug effects
  • Respiration / genetics
  • Rett Syndrome / drug therapy
  • Rett Syndrome / genetics
  • Rett Syndrome / metabolism*
  • Rett Syndrome / physiopathology*
  • Transfection
  • Up-Regulation / genetics


  • Kcnj10 (channel)
  • Kir5.1 channel
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Potassium Channels, Inwardly Rectifying
  • Carbon Dioxide
  • Desipramine
  • Norepinephrine