Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 28, Issue 11, Pages 1835-1844Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2008.71
Keywords
adenosine; glia; ischemia; penumbra; spreading depression
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Funding
- Spanish Ministry of Education and Science [BFU 2005/8917, BFU2006-28426-E/BFI]
- Comunidad Autonoma de Madrid [S-SEM-0255-2006]
- Consejo Superior de Investigaciones Cientificas [I3/200620I186]
- Human Frontier Science Program
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In a model of glial-specific chemical anoxia, we have examined how astrocytes influence both synaptic transmission and the viability of hippocampal pyramidal neurons. This relationship was assessed using electrophysiological, pharmacological, and biochemical techniques in rat slices and cell cultures, and oxidative metabolism was selectively impaired in glial cells by exposure to the mitochondrial gliotoxin, fluoroacetate. We found that synaptic transmission was blocked shortly after inducing glial metabolic stress and peri-infarct-like spreading depression (SD) waves developed within 1 to 2 h of treatment. Neuronal electrogenesis was not affected until SD waves developed, thereafter decaying irreversibly. The blockage of synaptic transmission was totally reversed by A(1) adenosine receptor antagonists, unlike the development of SD waves, which appeared earlier under these conditions. Such blockage led to a marked reduction in the electrical viability of pyramidal neurons 1 h after gliotoxin treatment. Cell culture experiments confirmed that astrocytes indeed release adenosine. We interpret this early glial response as a novel safety mechanism that allocates metabolic resources to vital processes when the glia itself sense an energy shortage, thereby delaying or preventing entry into massive lethal ischemic-like depolarization. The implication of these results on the functional recovery of the penumbra regions after ischemic insults is discussed.
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