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The Journal of Neuroscience, January 26, 2005, 25(4):848-859; doi:10.1523/JNEUROSCI.4157-04.2005

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Neurobiology of Disease
A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

Nicola J. Allen, ^* Ragnhildur Káradóttir, ^* and David Attwell

Department of Physiology, University College London, London WC1E 6BT, United Kingdom

During brain anoxia or ischemia, a decrease in the level of ATP leads to a sudden decrease in transmembrane ion gradients [anoxic depolarization (AD)]. This releases glutamate by reversing the operation of glutamate transporters, which triggers neuronal death. By whole-cell clamping CA1 pyramidal cells, we investigated the energy stores that delay the occurrence of the AD in hippocampal slices when O₂ and glucose are removed. With glycolytic and mitochondrial ATP production blocked in P12 slices, the AD occurred in 7 min at 33°C, reflecting the time needed for metabolic activity to consume the existing ATP and phosphocreatine, and for subsequent ion gradient decrease. Allowing glycolysis fueled by glycogen, in the absence of glucose, delayed the AD by 5.5 min, whereas superfused glucose prevented the AD for >1 h. With glycolysis blocked, the latency to the AD was 6.5 min longer when mitochondria were allowed to function, demonstrating that metabolites downstream of glycolysis (pyruvate, citric acid cycle intermediates, and amino acid oxidation) provide a significant energy store for oxidative phosphorylation. With glycolysis blocked but mitochondria functioning, superfusing lactate did not significantly delay the AD, showing that ATP production from lactate is much less than that from endogenous metabolites. These data demonstrate a preferential role for glycolysis in preventing the AD. They also define a hierarchy of pool sizes for hippocampal energy stores and suggest that brain ATP production from glial lactate may not be significant in conditions of energy deprivation.

Key words: anoxia; ischemia; lactate; ATP; anoxic depolarization; glucose

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Received June 2, 2004; revised November 30, 2004; accepted December 1, 2004.

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