Metabolic Trafficking between Neurons and Astrocytes: The Glutamate/Glutamine Cycle Revisited

Use of 13C-labeled precursors for the neuroactive amino acids glutamate and GABA as well as [U-13C]glutamate and glutamine combined with NMR spectroscopy has allowed detailed studies to be performed on cultured neurons and astrocytes yielding new information about synthesis and metabolism of these amino acids at the cellular level. Thus, it has become clear that astrocytes metabolize glutamate extensively through the tricarboxylic acid (TCA) cycle in a rather complex manner enabling the cells to generate lactate from malate. It has been shown that astrocytes can supply neurons not only with glutamine but also with TCA cycle constituents, lactate and alanine. Hence, an extended version of the glutamate/glutamine cycle is presented. Moreover, it has been demonstrated that citrate synthesized in astrocytes and released into the extracellular space can modify neuronal activity by regulating the Zn2+ concentration and thereby modulate N-methyl-D-aspartate receptor-mediated depolarization.