title: The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome.
abstract: 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.
authors.affiliation: Dept. of Biology, Georgia State Univ., Atlanta, 30303, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Junda
authors.initials: J
authors.lastname: Su
authors.forename: Ningren
authors.initials: N
authors.lastname: Cui
authors.forename: Hongyu
authors.initials: H
authors.lastname: Gai
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Wu
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism* / Q000494:pharmacology; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000502:physiology*; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D017097:Electric Impedance; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000503:physiopathology; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D008168:Lung / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012119:Respiration / Q000187:drug effects / Q000235:genetics; D015518:Rett Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics; D000097062:Kir5.1 Channel; D000098854:Kcnj10 Channel
chemical_list: D002245:Carbon Dioxide; D003891:Desipramine; D051783:Methyl-CpG-Binding Protein 2; D009638:Norepinephrine; D024661:Potassium Channels, Inwardly Rectifying; D000097062:Kir5.1 Channel; D000098854:Kcnj10 Channel; C497393:Mecp2 protein, mouse