Sweet and sour recipes for the brain. 1. “Sweet slices are fine”?

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!

Is glucose the absolutely exclusive fuel for the brain? In popular articles, you might always read that yes, it is.

Meanwhile, in special scientific literature the role of quite a few energy carriers including ketone bodies (mostly beta-hydroxybutirate, BHB), lactate, and pyruvate was unquestioned for decades. Recently, a series of three research reports published in the Journal of Neuroscience (Tyzio et al., 2011, Ruusuvuori et al., 2010 and Kirmse et al., 2010) arrived at the conclusion contradicting to the well known fact about brain energy metabolism in neonates. It seemed indisputable that in the neonatal brain, the use of glucose as an energy substrate is limited due to immaturity of the mechanisms of glucose utilization but the articles in question shed doubts on it. Why is it important to sort out these conflicting research results?

I already wrote about the importance of energy substrates other than glucose for the immature brain and the consequence of ignoring this role in experiments on neonatal brain slices discussing the results of Rheims et al., 2009 and Holmgren et al., 2010.

In 2010, at the meeting of the Society for Neuroscience in San Diego, CA, a poster has been presented announcing in its title: “BHB does not alter GABA signals in neonatal slices: sweet slices are fine, no need to alter conventional ACSF“. Neither poster nor its abstract (Picardo et al., 2010) contained methodical details and they remained unknown until 2011 when an article in the Journal of Neuroscience was published (Tyzio et al., 2011). It became possible to compare the differences in methods, which has been done in due time and published in the Frontiers in Neuroenergetics (Ivanov et al., 2011) — see parts 2-4.

Important is, that Ivanov et al. showed that in immature brain slices, glucose rendered less efficient energy carrier than lactate, BHB, and pyruvate.  Judged by the hallmarks of energy metabolism – oxygen utilization and nicotinamide adenine dinucleotide phosphate or NAD(P)H, neuronal activity robustness was higher in the presence of lactate alone or combined with glucose than with glucose alone. The authors concluded: “We show that in the presence of glucose, lactate is effectively utilized as an energy substrate, causing an  augmentation of oxidative metabolism. Moreover, in the absence of glucose lactate is fully capable of maintaining synaptic function. Therefore, during network activity in neonatal slices, lactate can be  an efficient energy substrate capable of sustaining and enhancing aerobic energy metabolism.”

References

  1. Garcia, A.J., 3rd, Putnam, R.W., and Dean, J.B. (2010). Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons. J Appl Physiol 109, 804-819.
  2. Hajos, N., Ellender, T.J., Zemankovics, R., Mann, E.O., Exley, R., Cragg, S.J., Freund, T.F., and Paulsen, O. (2009). Maintaining network activity in submerged hippocampal slices: importance of oxygen supply. Eur J Neurosci 29, 319-327.
  3. Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y (2010) Energy substrate availability as a determinant of neuronal resting potential,GABAsignaling and spontaneous network activity in the neonatal cortex in vitro. J Neurochem 112:900 –912.
  4. Ivanov A, Mukhtarov M, Bregestovski P and Zilberter Y (2011). Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices. Front. Neuroenerg. 3:2.
  5. Kirmse K, Witte OW, Holthoff K. (2010). GABA Depolarizes Immature Neocortical Neurons in the Presence of the Ketone Body β-Hydroxybutyrate. J Neuroscience, 24; 30(47): 16002-16007
  6. Lehninger, A.L. (2005). “Oxydative phosphorylation and photophosphorylation,” in Principles of biochemistry, eds. D.L. Nelson & M.M. Cox. Forth ed: W. H. Freeman), 690-740.
  7. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y (2009) GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. J Neurochem 110: 1330–1338.
  8. Schurr, A., and Payne, R.S. (2007). Lactate, not pyruvate, is neuronal aerobic glycolysis end product: an in vitro electrophysiological study. Neuroscience 147, 613-619.
  9. Tyzio, R., Allene, C., Nardou, R., Picardo, M.A., Yamamoto, S., Sivakumaran, S., Caiati, M.D., Rheims, S., Minlebaev, M., Milh, M., Ferre, P., Khazipov, R., Romette, J.L., Lorquin, J., Cossart, R., Khalilov, I., Nehlig, A., Cherubini, E., and Ben-Ari, Y. (2011). Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate. J Neurosci 31, 34-45.
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