Figure 1.

The first picture of the astrocyte–neuron lactate shuttle (ANLS) model at birth on 25 October 1994. Schematic of the mechanism for glutamate-induced glycolysis in astrocytes during physiological activation. At glutamatergic synapses, glutamate depolarizes neurons by acting at specific receptor subtypes. The action of glutamate is terminated by an efficient glutamate uptake system located primarily in astrocytes. Glutamate is cotransported with Na⁺, resulting in an increase in [Na⁺]_i, leading to activation of Na⁺/K⁺ ATPase. The pump, fueled by ATP provided by membrane-bound glycolytic enzymes (possibly phosphoglycerate kinase (PGK)), activates glycolysis—that is, glucose utilization and lactate production—in astrocytes. Lactate, once released, can be taken up by neurons and serve as an adequate energy substrate. For graphic clarity, only lactate uptake into presynaptic terminals is indicated. However, this process could also occur at the postsynaptic neuron. Based on recent evidence, glutamate receptors are also shown on astrocytes. This model, which summarizes in vitro experimental evidence indicating glutamate-induced glycolysis, is taken to reflect cellular and molecular events occurring during activation of a given cortical area [arrow labeled A (activation)] direct glucose uptake into neurons under basal conditions is also shown [arrow labeled B (basal conditions)]. Pyr, pyruvate; LAC, lactate; GLN, glutamine; G, guanine nucleotide binding protein. Taken from Pellerin and Magistretti (1994).