期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 9, 页码 2403-2414出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0005-16.2016
关键词
astrocyte; calcium; cerebral blood flow; glutathione; hypercapnia
资金
- Sir Henry Wellcome Post-Doctoral Fellowship
- Government of Canada Post-Doctoral Research Fellowship
- Michael Smith Foundation for Health Research Post-Doctoral Fellowship
- Natural Sciences and Engineering Research Council Post-Doctoral Fellowship
- Canadian Institutes of Health Research Doctoral Studentship
- Canada Research Chair in Neuroscience
- Canadian Institutes of Health Research [148397, 8545, 115121]
- ERA-NET NEURON [TCE-117869]
- Fondation Leducq
- Human Frontiers Science Program
- National Institutes of Health [GM053395, NS069720]
- Heart and Stroke Foundation
- Wellcome Trust
- Royal Society University Research Fellowship
- Cancer Research United Kingdom [C5255/A12678]
- Henry Smith Charity
- NORDEA Foundation for the Center for Healthy Aging
- Lundbeck Foundation
- NOVO-Nordisk Foundation
- Danish Medical Research Council
- Cancer Research UK [16945] Funding Source: researchfish
- Lundbeck Foundation [R210-2015-3320] Funding Source: researchfish
- Medical Research Council [G0401355] Funding Source: researchfish
- MRC [G0401355] Funding Source: UKRI
Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O-2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1 mm Hg variation in arterial CO2 changes CBF by 3%-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E-2 (PgE(2)) plays a key role for cerebrovascular CO2 reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57BL/6J mice to examine the hemodynamic responses to CO2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2 synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+](i) and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE(2) (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by increased astrocyte [Ca2+](i) in vitro and by hypercapnia in vivo is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2. Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.
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