Figure 5.

The Astrocyte-Neuron Lactate Shuttle Hypothesis of activity-dependent regulation of neuronal energy substrate supply by astrocytes. At excitatory synapses, glutamate is released in the synaptic cleft upon activation. Its action on post-synaptic receptors is terminated by its reuptake in astrocytes through high affinity, glial-specific glutamate transporters (EAATs). Glutamate is converted into glutamine and released by astrocytes via a specific glial glutamine transporter. Glutamine will be taken up by neurons from the extracellular space via a neuron-specific glutamine transporter and glutamine will be converted to glutamate before being accumulated in synaptic vesicles. In parallel, glutamate uptake into astrocytes will trigger an increase in glycolysis, with an enhancement of glucose uptake from the blood circulation into astrocytes via specific glucose transporters (GLUTs) on both endothelial cells and astrocytes. Lactate produced by astrocytes will be released in the extracellular space. To face their increased energy demands following synaptic activation, neurons will take up more lactate and oxidize it to produce more ATP. Neurons also take up glucose from the circulation via a specific glucose transporter. Part of the glucose can be metabolized through glycolysis and then oxidized in mitochondria to provide ATP. However, a significant amount of glucose is metabolized in neurons through the Pentose Phosphate Pathway (PPP) in order to regenerate NADPH necessary as cofactor for enzymes involved in antioxidant defenses.