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The Journal of Neuroscience, April 4, 2007, 27(14):3618-3625; doi:10.1523/JNEUROSCI.0132-07.2007

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Neurobiology of Disease
Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening K_ATP Channels

Weiyuan Ma, Jim Berg, and Gary Yellen

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Gary Yellen, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: gary_yellen{at}hms.harvard.edu

A low-carbohydrate ketogenic diet remains one of the most effective (but mysterious) treatments for severe pharmacoresistant epilepsy. We have tested for an acute effect of physiological ketone bodies on neuronal firing rates and excitability, to discover possible therapeutic mechanisms of the ketogenic diet. Physiological concentrations of ketone bodies (ß-hydroxybutyrate or acetoacetate) reduced the spontaneous firing rate of neurons in slices from rat or mouse substantia nigra pars reticulata. This region is thought to act as a "seizure gate," controlling seizure generalization. Consistent with an anticonvulsant role, the ketone body effect is larger for cells that fire more rapidly. The effect of ketone bodies was abolished by eliminating the metabolically sensitive K_ATP channels pharmacologically or by gene knock-out. We propose that ketone bodies or glycolytic restriction treat epilepsy by augmenting a natural activity-limiting function served by K_ATP channels in neurons.

Key words: epilepsy; ketogenic diet; K_ATP channels; substantia nigra pars reticulata; glycolysis; anticonvulsant treatment

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Received Jan. 11, 2007; revised Feb. 13, 2007; accepted Feb. 22, 2007.

Correspondence should be addressed to Dr. Gary Yellen, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: gary_yellen{at}hms.harvard.edu

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