Theoretical support for the astrocyte-neuron lactate shuttle hypothesis. I. Modeling neuronal and astrocytic NADH/NAD + kinetics

Introduction

The question of the compartmentalization of brain energy metabolism has been the subject of intense debate for the past decade, with the astrocyte-neuron lactate shuttle (ANLS) hypothesis, proposed by Pellerin and Magistretti ¹ , which assumes that astrocytes can provide lactate as an energy fuel to neurons. Some authors challenged this hypothesis, defending the classical view that glucose is the major energy substrate of neurons, at rest as well as in response to a stimulation ² . An important aspect of this discussion is the role that NADH might play in brain energy metabolism, since it is produced by glycolysis and both consumed by lactate dehydrogenase-catalyzed reaction and by mitochondria. In order to assess neuronal and astrocytic NADH/NAD+ ratio changes and then test the ANLS hypothesis from a theoretical point of view, we developed a mathematical model of compartmentalized energy metabolism between neurons and astrocytes ³ .

Method

On the basis of a previously validated model ⁴ , which describes the relationships between brain activation, energy metabolism and hemodynamics within the brain tissue, we distinguished between neuronal, astrocytic, extracellular and vascular compartments. We adopted hypotheses highly unfavorable to ANLS, e.g. we assumed that at steady state neurons do not take up lactate and the regulation of mitochondrial activity is the same in both neurons and astrocytes. Most variable and parameter values were chosen to be the same for neurons and astrocytes, except a moderate lactate efflux from astrocytes at rest, and a slightly higher NADH/NAD+ ratio in astrocytes at rest.

Results and Discussion

Simulation results can be divided between two groups, depending on the relative neuron versus astrocyte stimulation. If this ratio is low, ANLS is observed during all the stimulus and post-stimulus period (continuous ANLS), but a high ratio induces ANLS only at the beginning of the stimulus and during the post-stimulus period (triphasic behavior). Finally, our results show that (i) current experimental data on brain lactate kinetics^{5, 6} are compatible with the ANLS hypothesis, and (ii) occurrence of ANLS may greatly depend on the neuronal and astrocytic NADH/NAD+ ratio changes. These theoretical results are fully consistent with the recent experimental data of Kasischke et al. ⁷ , who used a two-photon fluorescence imaging of NADH in hippocampal slices. These authors showed that, in response to a short activation, dendrites undergo an early oxidation, followed by a significant reduction in astrocyte cytoplasm. This sequence of events agrees with a net lactate transfer between astrocytes and neurons as predicted by the ANLS.