Neurons rely on glucose rather than astrocytic lactate during stimulation

Abstract

Brain metabolism increases during stimulation, but this increase does not affect all energy metabolism equally. Briefly after stimulation, there is a local increase in cerebral blood flow and in glucose uptake, but a smaller increase in oxygen uptake. This indicates that temporarily the rate of glycolysis is faster than the rate of oxidative metabolism, with a corresponding temporary increase in lactate production. This minireview discusses the long-standing controversy about which cell type, neurons or astrocytes, are involved in this increased aerobic glycolysis. Recent biosensor studies measuring metabolic changes in neurons, in acute brain slices or in vivo, are placed in the context of other data bearing on this question. The most direct measurements indicate that, although both neurons and astrocytes may increase glycolysis after stimulation, neurons do not rely on import of astrocytic-produced lactate, and instead they increase their own glycolytic rate and become net exporters of lactate. This temporary increase in neuronal glycolysis may provide rapid energy to meet the acute energy demands of neurons.

Figure 1.. Two hypotheses for how neurons respond metabolically to stimulation.

One is that stimulated astrocytes produce lactate, which is then utilized by neurons (ANLS hypothesis, blue arrows). The other is that stimulated neurons themselves use glucose to perform glycolysis (red arrows). The insets depict the behavior of the biosensor data from Díaz-García et al. (2017). They show that stimulation leads to an elevation in neuronal NADH_CYT and Lactate_CYT (solid lines); these changes are consistent with both hypotheses. When the monocarboxylate transporter (MCT) is inhibited, however, NADH_CYT transients become larger, and Lac_CYT transients are preserved. This is inconsistent with the ANLSH, which predicts that they should diminish or disappear. The accumulation of NADH_CYT and Lac_CYT is instead due to direct neuronal glycolysis. The NADH_CYT transient is enhanced because MCT blockade prevents export of lactate that would normally relieve accumulation on the NADH_CYT ; the enhancement is even greater with blockade of LDH. The dips in neuronal cytosolic glucose, produced by an increased glycolytic rate, indicate that rather than being upregulated by MCT blockade (and putative deprivation of astrocytic lactate), neuronal glycolysis is diminished by buildup of NADH_CYT. Time scale bar = 1 min.