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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 /[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 [Ca2+]i in astrocytes residing near the ventral surface of the medulla oblongata. The magnitude of CO2-induced [Ca2+]i responses in medullary astrocytes was markedly reduced in conditions of MeCP2 deficiency, whereas [Ca2+]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 /[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.
Original language | English |
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Pages (from-to) | 3159-3168 |
Number of pages | 10 |
Journal | Journal of Physiology |
Volume | 593 |
Issue number | 14 |
Early online date | 17 Jun 2015 |
DOIs | |
Publication status | Published - 15 Jul 2015 |
Fingerprint
Dive into the research topics of 'Impaired CO2 sensitivity of astrocytes in a mouse model of Rett syndrome'. Together they form a unique fingerprint.Projects
- 1 Finished
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IRSF Advanced Neuro-therapeutic Grant of Excellence Award: Novel highly selective and potent serotonergic 1a receptor agonist for the treatment of Rett Syndrome in murine models: a pre-clinical study
Abdala Sheikh, A. P. (Co-Principal Investigator) & Paton, J. F. R. (Co-Principal Investigator)
1/08/14 → 31/07/16
Project: Research
Profiles
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Dr Ana Paula Abdala Sheikh
- School of Physiology, Pharmacology & Neuroscience - Senior Lecturer
Person: Academic