Availability of neurotransmitter glutamate is diminished when β-hydroxybutyrate replaces glucose in cultured neurons
Article first published online: 18 MAY 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 110, Issue 1, pages 80–91, July 2009
How to Cite
Lund, T. M., Risa, Ø., Sonnewald, U., Schousboe, A. and Waagepetersen, H. S. (2009), Availability of neurotransmitter glutamate is diminished when β-hydroxybutyrate replaces glucose in cultured neurons. Journal of Neurochemistry, 110: 80–91. doi: 10.1111/j.1471-4159.2009.06115.x
- Issue published online: 15 JUN 2009
- Article first published online: 18 MAY 2009
- Received November 21, 2008; revised manuscript received April 1, 2009; accepted April 8, 2009.
- ketone bodies;
Ketone bodies serve as alternative energy substrates for the brain in cases of low glucose availability such as during starvation or in patients treated with a ketogenic diet. The ketone bodies are metabolized via a distinct pathway confined to the mitochondria. We have compared metabolism of [2,4-13C]β-hydroxybutyrate to that of [1,6-13C]glucose in cultured glutamatergic neurons and investigated the effect of neuronal activity focusing on the aspartate–glutamate homeostasis, an essential component of the excitatory activity in the brain. The amount of 13C incorporation and cellular content was lower for glutamate and higher for aspartate in the presence of [2,4-13C]β-hydroxybutyrate as opposed to [1,6-13C]glucose. Our results suggest that the change in aspartate–glutamate homeostasis is due to a decreased availability of NADH for cytosolic malate dehydrogenase and thus reduced malate–aspartate shuttle activity in neurons using β-hydroxybutyrate. In the presence of glucose, the glutamate content decreased significantly upon activation of neurotransmitter release, whereas in the presence of only β-hydroxybutyrate, no decrease in the glutamate content was observed. Thus, the fraction of the glutamate pool available for transmitter release was diminished when metabolizing β-hydroxybutyrate, which is in line with the hypothesis of formation of transmitter glutamate via an obligatory involvement of the malate–aspartate shuttle.