title: Impaired CO2 sensitivity of astrocytes in a mouse model of Rett syndrome.
abstract: Rett syndrome, a prototypical neurological disorder caused by loss of function of the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) gene, is associated with a severely disordered breathing pattern and reduced ventilatory CO2 sensitivity. In a mouse model of Rett syndrome (MeCP2 knockout), re-introduction of the MeCP2 gene selectively in astrocytes rescues normal respiratory phenotype. In the present study we determined whether the metabolic and/or signalling functions of astrocytes are affected by testing the hypotheses that in conditions of MeCP2 deficiency, medullary astrocytes are unable to produce/release appropriate amounts of lactate or detect changes in PCO2/[H(+) ], or both. No differences in tonic or hypoxia-induced release of lactate from the ventral surface of the medulla oblongata or cerebral cortex in brain slices of MeCP2-knockout and wild-type mice were found. In brainstem slices of wild-type mice, respiratory acidosis triggered robust elevations in [Ca(2+) ]i in astrocytes residing near the ventral surface of the medulla oblongata. The magnitude of CO2 -induced [Ca(2+) ]i responses in medullary astrocytes was markedly reduced in conditions of MeCP2 deficiency, whereas [Ca(2+) ]i responses to ATP were unaffected. These data suggest that (i) metabolic function of astrocytes in releasing lactate into the extracellular space is not affected by MeCP2 deficiency, and (ii) MeCP2 deficiency impairs the ability of medullary astrocytes to sense changes in PCO2/[H(+) ]. Taken together with the evidence of severely blunted ventilatory sensitivity to CO2 in mice with conditional MeCP2 deletion in astroglia, these data support the hypothesis of an important role played by astrocytes in central respiratory CO2 /pH chemosensitivity.
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.|Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.
authors.forename: Egor
authors.initials: E
authors.lastname: Turovsky
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Anastassios
authors.initials: A
authors.lastname: Karagiannis
authors.affiliation: School of Physiology & Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abdala
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008526:Medulla Oblongata / Q000166:cytology / Q000378:metabolism; D051379:Mice; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D002245:Carbon Dioxide; D019344:Lactic Acid; C107407:Mesp2 protein, mouse