Mechanistic stoichiometric relationship between the rates of neurotransmission and neuronal glucose oxidation: Reevaluation of and alternatives to the pseudo‐malate‐aspartate shuttle model

The ~1:1 stoichiometry between the rates of neuronal glucose oxidation (CMRglc-ox-N) and glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) neurotransmitter (NT) cycling between neurons and astrocytes (VNTcycle) has been firmly established. However, the mechanistic basis for this relationship is not fully understood, and this knowledge is critical for the interpretation of metabolic and brain imaging studies in normal and diseased brain. The pseudo-malate-aspartate shuttle (pseudo-MAS) model established the requirement for glycolytic metabolism in cultured glutamatergic neurons to produce NADH that is shuttled into mitochondria to support conversion of extracellular Gln (i.e., astrocyte-derived Gln in vivo) into vesicular neurotransmitter Glu. The evaluation of this model revealed that it could explain half of the 1:1 stoichiometry and it has limitations. Modifications of the pseudo-MAS model were, therefore, devised to address major knowledge gaps, that is, submitochondrial glutaminase location, identities of mitochondrial carriers for Gln and other model components, alternative mechanisms to transaminate α-ketoglutarate to form Glu and shuttle glutamine-derived ammonia while maintaining mass balance. All modified models had a similar 0.5 to 1.0 predicted mechanistic stoichiometry between VNTcycle and the rate of glucose oxidation. Based on studies of brain β-hydroxybutyrate oxidation, about half of CMRglc-ox-N may be linked to glutamatergic neurotransmission and localized in pre-synaptic structures that use pseudo-MAS type mechanisms for Glu-Gln cycling. In contrast, neuronal compartments that do not participate in transmitter cycling may use the MAS to sustain glucose oxidation. The evaluation of subcellular compartmentation of neuronal glucose metabolism in vivo is a critically important topic for future studies to understand glutamatergic and GABAergic neurotransmission.