title: Functional Oxygen Sensitivity of Astrocytes.
abstract: In terrestrial mammals, the oxygen storage capacity of the CNS is limited, and neuronal function is rapidly impaired if oxygen supply is interrupted even for a short period of time. However, oxygen tension monitored by the peripheral (arterial) chemoreceptors is not sensitive to regional CNS differences in partial pressure of oxygen (PO2 ) that reflect variable levels of neuronal activity or local tissue hypoxia, pointing to the necessity of a functional brain oxygen sensor. This experimental animal (rats and mice) study shows that astrocytes, the most numerous brain glial cells, are sensitive to physiological changes in PO2 . Astrocytes respond to decreases in PO2 a few millimeters of mercury below normal brain oxygenation with elevations in intracellular calcium ([Ca(2+)]i). The hypoxia sensor of astrocytes resides in the mitochondria in which oxygen is consumed. Physiological decrease in PO2 inhibits astroglial mitochondrial respiration, leading to mitochondrial depolarization, production of free radicals, lipid peroxidation, activation of phospholipase C, IP3 receptors, and release of Ca(2+) from the intracellular stores. Hypoxia-induced [Ca(2+)]i increases in astrocytes trigger fusion of vesicular compartments containing ATP. Blockade of astrocytic signaling by overexpression of ATP-degrading enzymes or targeted astrocyte-specific expression of tetanus toxin light chain (to interfere with vesicular release mechanisms) within the brainstem respiratory rhythm-generating circuits reveals the fundamental physiological role of astroglial oxygen sensitivity; in low-oxygen conditions (environmental hypoxia), this mechanism increases breathing activity even in the absence of peripheral chemoreceptor oxygen sensing. These results demonstrate that astrocytes are functionally specialized CNS oxygen sensors tuned for rapid detection of physiological changes in brain oxygenation. Significance statement: Most, if not all, animal cells possess mechanisms that allow them to detect decreases in oxygen availability leading to slow-timescale, adaptive changes in gene expression and cell physiology. To date, only two types of mammalian cells have been demonstrated to be specialized for rapid functional oxygen sensing: glomus cells of the carotid body (peripheral respiratory chemoreceptors) that stimulate breathing when oxygenation of the arterial blood decreases; and pulmonary arterial smooth muscle cells responsible for hypoxic pulmonary vasoconstriction to limit perfusion of poorly ventilated regions of the lungs. Results of the present study suggest that there is another specialized oxygen-sensitive cell type in the body, the astrocyte, that is tuned for rapid detection of physiological changes in brain oxygenation.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Plamena R
authors.initials: PR
authors.lastname: Angelova
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Kasymov
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Christie
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Sheikhbahaei
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
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, London WC1E 6BT, United Kingdom.
authors.forename: Nephtali
authors.initials: N
authors.lastname: Marina
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Alla
authors.initials: A
authors.lastname: Korsak
authors.affiliation: Department of Physiology, Centre for Neuroscience and Women and Children's Health Research Institute, University of Alberta, Alberta, Edmonton, Canada T6G 2E1, and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zwicker
authors.affiliation: Department of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Anja G
authors.identifier: http://orcid.org/0000-0002-5514-2669
authors.initials: AG
authors.lastname: Teschemacher
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Gareth L
authors.identifier: http://orcid.org/0000-0003-0565-5164
authors.initials: GL
authors.lastname: Ackland
authors.affiliation: Department of Physiology, Centre for Neuroscience and Women and Children's Health Research Institute, University of Alberta, Alberta, Edmonton, Canada T6G 2E1, and.
authors.forename: Gregory D
authors.identifier: http://orcid.org/0000-0001-5848-0631
authors.initials: GD
authors.lastname: Funk
authors.affiliation: Department of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kasparov
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.affiliation: Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom, a.gourine@ucl.ac.uk.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Gourine
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002628:Chemoreceptor Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012143:Respiratory Physiological Phenomena
chemical_list: D010100:Oxygen
keywords: astrocyte; glia; hypoxia; oxygen; respiration