An increase in lactate output by brain tissue serves to meet the energy needs of glutamate-activated neurons

Aerobic energy metabolism uses glucose and oxygen to produce all the energy needs of the brain. Several studies published over the last 13 years chall enged the assumption that the activated brain increases its oxidative gluco se metabolism to meet the increased energy demands. Neuronal function in ra t hippocampal slices supplied with 4 mM glucose could tolerate a 15 min act ivation by a 5 mM concentration of the excitatory neurotransmitter glutamat e (Glu), whereas slices supplied with 10 mM glucose could tolerate a 15 min activation by 20 mM Glu. However, in slices in which neuronal lactate use was inhibited by the lactate transporter inhibitor a-cyano-4-hydroxycinnama te (4-ClN), activation by Glu elicited a permanent loss of neuronal functio n, with a twofold to threefold increase in tissue lactate content. Inhibiti on of glycolysis with the glucose analog 2-deoxy-D-glucose (2DG) during the period of exposure to Glu diminished normal neuronal function in the major ity of slices and significantly reduced the number of slices that exhibited neuronal function after activation. However, when lactate was added with 2 DG, the majority of the slices were neuronally functional after activation by Glu. NMDA, a nontransportable Glu analog by the glial glutamate transpor ter, could not induce a significant increase in slice lactate level when ad ministered in the presence of 4-ClN. It is suggested that the heightened en ergy demands of activated neurons are met through increased glial glycolyti c flux. The lactate thus formed is a crucial aerobic energy substrate that enables neurons to endure activation.