title: The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity.
abstract: Glucose is the main energy substrate for neurons, and ketone bodies are known to be alternative substrates. However, the capacity of ketone bodies to support different neuronal functions is still unknown. Thus, a change in energy substrate from glucose alone to a combination of glucose and β-hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body β-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of β-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when β-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of β-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of β-hydroxybutyrate augmented transmitter release induced by the KATP channel blocker glibenclamide, thus giving an indirect indication of the involvement of KATP channels in the effects of ketone bodies on transmitter release. Energy metabolism and neurotransmission are linked and involve ATP-sensitive potassium (KATP ) channels. However, it is still unclear how and to what degree available energy substrate affects this link. We investigated the effect of changing energy substrate from only glucose to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Trine M
authors.initials: TM
authors.lastname: Lund
authors.affiliation: Danish Headache Center, Department of Neurology and Research Institute, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Ploug
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Danish Headache Center, Department of Neurology and Research Institute, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Iversen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Danish Headache Center, Department of Neurology and Research Institute, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors.forename: Inger
authors.initials: I
authors.lastname: Jansen-Olesen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D006019:Glycolysis / Q000502:physiology*; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D054086:KATP Channels; D020155:3-Hydroxybutyric Acid
keywords: KATP channels; cultured neurons; glutamate; glycolysis; ketone bodies; β-hydroxybutyrate