Ketogenic diet sensitizes glucose control of hippocampal excitability

J Lipid Res. 2014 Nov;55(11):2254-60. doi: 10.1194/jlr.M046755. Epub 2014 Aug 28.


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.

Keywords: 8-cyclopentyl-1,3-dipropylxanthine; KATP channel; adenosine A1 receptors; bicuculline; epilepsy; ketones; metabolism; pannexin; purine; seizure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / physiology
  • CA3 Region, Hippocampal / physiopathology
  • Connexins / metabolism
  • Diet, Ketogenic*
  • Female
  • Gene Knockout Techniques
  • Glucose / metabolism*
  • Hippocampus / metabolism
  • Hippocampus / physiology*
  • Hippocampus / physiopathology
  • KATP Channels / metabolism
  • Male
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Rats
  • Receptor, Adenosine A1 / deficiency
  • Receptor, Adenosine A1 / genetics
  • Seizures / metabolism
  • Seizures / physiopathology
  • Seizures / prevention & control


  • Connexins
  • KATP Channels
  • Nerve Tissue Proteins
  • Panx1 protein, mouse
  • Receptor, Adenosine A1
  • Glucose