title: Ketogenic diet sensitizes glucose control of hippocampal excitability.
abstract: 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.
authors.affiliation: Department of Pharmacology, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Psychology Department and Neuroscience Program, Trinity College, Hartford, CT 06106.
authors.forename: David N
authors.initials: DN
authors.lastname: Ruskin
authors.affiliation: Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Geiger
authors.affiliation: Robert Stone Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR 97232.
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.affiliation: Psychology Department and Neuroscience Program, Trinity College, Hartford, CT 06106.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Masino
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D017630:Connexins / Q000378:metabolism; D055423:Diet, Ketogenic; D005260:Female; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000172:deficiency / Q000235:genetics; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D017630:Connexins; D054086:KATP Channels; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D043682:Receptor, Adenosine A1; D005947:Glucose
keywords: 8-cyclopentyl-1,3-dipropylxanthine; KATP channel; adenosine A1 receptors; bicuculline; epilepsy; ketones; metabolism; pannexin; purine; seizure