Editors' ChoiceNeuroscience

Food for Thought

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Science Signaling  16 Dec 2008:
Vol. 1, Issue 50, pp. ec437
DOI: 10.1126/scisignal.150ec437

When neurons in the brain get busy processing information, all the pumping of ions required for firing action potentials uses large amounts of energy, which the neurons gain from oxygen and glucose supplied in the blood. Gordon et al. provide new insights into the intricate system through which signaling between neurons, their supporting astrocytes, and smooth muscle cells controls blood flow in arterioles. Glutamate released from neurons causes increases in the intracellular concentration of Ca2+ in astrocytes, thereby activating phospholipase A2, which produces arachidonic acid. But arachidonic acid can be converted in muscle cells to 20-hydroxyeicosatetraenoic acid (20-HETE), which causes constriction of smooth muscle cells (which would inappropriately cut off blood supply to the active neurons) or in astrocytes to prostaglandin E2 (PGE2), which causes vasodilation (thus enhancing the supply of energy and oxygen to the neurons). Gordon et al. sought to understand how this system “knows” how to respond properly to changes in the local neuronal activity and find that it depends, in turn, on changes in oxygen pressure. Cells deprived of oxygen alter their metabolism, and the authors confirmed an expected increase in production of extracellular lactate (produced by glycolysis in astrocytes when oxygen concentrations fall) in rat brain slices exposed to low concentrations of O2. Pharmacological inhibition of glycolysis or lactate dehydrogenase decreased the amount of extracellular lactate. Because lactate inhibits prostaglandin transporters, this increased the amount of extracellular PGE2 as well. Thus, in low concentrations of O2, prostaglandin concentrations increase and arterioles become dilated. Experiments with pharmacological inhibitors of prostaglandin transporters confirmed that efficacy of prostaglandin transport controlled the abundance of PGE2 and thus vascular tone. The authors also imaged the intrinsic fluorescence of the electron carrier nicotinamide adenine dinucleotide (NADH) to confirm that low O2 concentrations increased glycolysis in astrocytes. But what about the vasoconstricting arm of the arachidonic acid pathway? The authors reasoned that when deprived of oxygen, cells make less adenosine triphosphate and adenosine accumulates extracellularly. Binding of adenosine to receptors on smooth muscle inhibits Ca2+ signaling and thus prevents constriction. They confirmed increased production of adenosine by monitoring adenosine receptor activity and showed that, in the presence of added adenosine, uncaging of bound Ca2+ in astrocytes failed to produce vasoconstriction. Helpful commentary by Hall and Attwell helps integrate the mechanisms presented with other switching mechanisms that influence blood flow in response to changes in oxygen pressure and points out that, because many experimental studies are done in abnormally high concentrations of O2, interpretation of the properties of the various signaling pathways involved must be done with caution.

G. R. J. Gordon, H. B. Choi, R. L. Rungta, G. C. R. Ellis-Davies, B. A. MacVicar, Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008). [PubMed]

C. N. Hall, D. Attwell, Brain power. Nature 456, 715–716 (2008). [Online Journal]

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