Ketogenic diet sensitizes glucose control of hippocampal excitability

Masahito Kawamura, David N. Ruskin, Jonathan D. Geiger, Detlev Boison, Susan A. Masino

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


A high-fat low-carbohydrate ketogenic diet (KD) is an effective treatment for refractory epilepsy, yet myriad metabolic effects in vivo have not been reconciled clearly with neuronal effects. A KD limits blood glucose and produces ketone bodies from β-oxidation of lipids. Studies have explored changes in ketone bodies and/or glucose in the effects of the KD, and glucose is increasingly implicated in neurological conditions. To examine the interaction between altered glucose and the neural effects of a KD, we fed rats and mice a KD and restricted glucose in vitro while examining the seizure-prone CA3 region of acute hippocampal slices. Slices from KD-fed animals were sensitive to small physiological changes in glucose, and showed reduced excitability and seizure propensity. Similar to clinical observations, reduced excitability depended on maintaining reduced glucose. Enhanced glucose sensitivity and reduced excitability were absent in slices obtained from KD-fed mice lacking adenosine A1 receptors (A1Rs); in slices from normal animals effects of the KD could be reversed with blockers of pannexin-1 channels, A1Rs, or KATP channels. Overall, these studies reveal that a KD sensitizes glucose-based regulation of excitability via purinergic mechanisms in the hippocampus and thus link key metabolic and direct neural effects of the KD.

Original languageEnglish (US)
Pages (from-to)2254-2260
Number of pages7
JournalJournal of Lipid Research
Issue number11
StatePublished - 2014
Externally publishedYes


  • 8-Cyclopentyl-1,3-dipropylxanthine
  • Adenosine A receptors
  • Bicuculline
  • Epilepsy
  • K channel
  • Ketones
  • Metabolism
  • Pannexin
  • Purine
  • Seizure

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology


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