The metabolic impact of β‐hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and K_ATP 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 b-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 b-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of b-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when b-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of b-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of b-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.

Ketones Prevent Oxidative Impairment of Hippocampal Synaptic Integrity through KATP Channels

“…Our findings that ketone application in 10 mM glucose-dissolved physiological saline and culture media containing 5.5 mM glucose conferred neuronal protection and synaptic restoration through K ATP channels was somewhat surprising since earlier studies demonstrated that the normal brain glucose detected range of 0.82 to 2.4 mM [ 49 ] and the hyperglycemia actually negated the open probability of K ATP channels [ 50 ]. On the other hand, Lund et al [ 51 ] recently reported that neurons cultured in BHB resulted in a strong alleviation of glycolytic intervention, likely by suppressing glucose metabolism seen with ketones [ 52 ]. While there is no direct evidence to elucidate the functional interplay between ATP level and glycolytic activity within ketone application, we cannot exclude the possibility that the decreased ATP supply originating from the glycolysis pathway may be indirectly responsible for enhancing the opening probability of K ATP channels.…”

Antiepileptic effects of exogenous β‑hydroxybutyrate on kainic acid‑induced epilepsy

“…Lower glycolytic ATP levels would lead to higher K ATP channel opening probability, which would cause membrane hyperpolarization and reduce the influx of calcium via voltage-gated calcium channels. This would in turn reduce the release of excitatory amino acids and decreased neuron excitability (44)(45)(46). K ATP channels, which are widely distributed in the hippocampus, would open with higher probability in the presence of BHB, which may underlie the anticonvulsive effects of ketone bodies.…”

Intestinal peroxisomal fatty acid β-oxidation regulates neural serotonin signaling through a feedback mechanism

“…For example, hypothalamic Kir6.2 KATP channels are responsive to circulating glucose levels and regulate appetite and glucose homeostasis [124][125][126]. Ketogenic diets, which increase circulating ketone body levels, have been shown to suppress the excitability of GABAergic neurons and reduce seizure susceptibility in a KATP channel dependent manner [127][128][129]. Numerous metabolites including phospholipids, polyunsaturated fatty acids, eicosanoids, fatty acyl-CoAs and oxygen can directly bind certain potassium channels to modulate channel activity [130][131][132].…”