Trafficking between glia and neurons of TCA cycle intermediates and related metabolites

Net synthesis of the neurotransmitter amino acids glutamate and GABA can take place either from glutamine or from alpha-ketoglutarate or another tricarboxylic acid (TCA) cycle intermediate plus an amino acid as donor of the amino group. Since neurons lack the enzymes glutamine synthetase and pyruvate carboxylase that are expressed only in astrocytes, trafficking of these metabolites must take place between neurons and astrocytes. Moreover, it is likely that astrocytes play an important role in maintaining the energy status in neurons supplying energy substrates, e.g., in the form of lactate. The role of trafficking of glutamine, TCA cycle constituents as well as the role of lactate as an energy source in neurons is discussed. Using [U-13C] lactate and NMR spectroscopy, it is shown that lactate that can be produced in astrocytes can be taken up into neurons and metabolized through the TCA-cycle leading to labeling of TCA cycle intermediates plus amino acids derived from these. The labeling pattern of glutamate and GABA indicates that C atoms from lactate remain in the cycle for several turns and that GABA formation may involve more than one glutamate pool, i.e., that compartmentation may exist. Additionally, a possible role of citrate as a chelator of Zn++ with regard to neuronal excitation is discussed. Astrocytes produce large quantities of citrate which by chelation of Zn++ alters the excitable state of neurons via regulation of N-methyl-D-aspartate receptor activity. Thus, astrocytes may regulate neuronal activity at a number of different levels.