title: Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice.
abstract: Mice that are deficient in the transcription factor methyl-CpG-binding protein 2 (MeCP2) have a depressed hypercapnic ventilatory response (HCVR). The expression of MeCP2 can be selectively removed from astrocytes or neurons, thus offering a tool to dissect the role of this transcription factor in astrocytes from that in neurons. Studies were carried out in the progeny of mice that were a cross between those harboring a tamoxifen (TAM)-inducible Cre recombinase transgene driven by the human astrocytic glial fibrillary acidic protein (hGFAP) promoter, or Cre recombinase under control of the synapsin promoter, with mice containing a Cre-excisable exon III in the Mecp2 gene. The TAM-conditional excision of the Mecp2 exon allowed the respiratory CO2 response to be studied in the same animals before and after selective depletion of MeCP2 in astrocytes. Immunohistochemistry showed that following TAM treatment only ∼20% of GFAP-labeled cells in the retrotrapazoid nucleus and in the raphé magnus were positive for MeCP2. The slope of the relative increase in minute ventilation as a function of 1, 3, and 5% inspired CO2 was depressed in mice with depleted astrocyte MeCP2 compared with wild-type littermates. In contrast, selective depletion of MeCP2 in neurons did not significantly affect slope. While neurons which constitute the respiratory network ultimately determine the ventilatory response to CO2, this study demonstrates that loss of MeCP2 in astrocytes alone is sufficient to result in a dramatic attenuation of the HCVR. We propose that the glial contribution to HCVR is under the control of the MeCP2 gene.
authors.affiliation: Vollum Institute, Howard Hughes Medical Institute.
authors.forename: Saurabh K
authors.initials: SK
authors.lastname: Garg
authors.affiliation: Vollum Institute, Howard Hughes Medical Institute.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Lioy
authors.affiliation: Department of Obstetrics and Gynecology, and.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Knopp
authors.affiliation: Department of Obstetrics and Gynecology, and Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, Oregon bissonne@ohsu.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Bissonnette
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism; D002478:Cells, Cultured; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006935:Hypercapnia / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D002245:Carbon Dioxide
keywords: Rett syndrome; astrocyte; hypercapnic ventilatory response