The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity

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 beta-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 beta-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of beta-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when beta-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of beta-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of beta-hydroxybutyrate augmented transmitter release induced by the K-ATP channel blocker glibenclamide, thus giving an indirect indication of the involvement of K-ATP channels in the effects of ketone bodies on transmitter release.