Metabolic control of brain energy and neurotransmitter metabolism

In vivo NMR spectroscopy is a powerful, non-invasive technique to study (human) brain metabolism. Proton NMR allows the detection of the neurotransmitters glutamate and g-aminobutyric acid (GABA), the endproduct of anaerobic glycolysis, lactic acid and an intermediate of glutamatergic neurotransmission, glutamine. In combination with carbon-13 and phosphorus-31 NMR, which can detect glycogen and ATP and phosphocreatine, respectively, in vivo NMR spectroscopy gives a complete overview of metabolites involved in excitatory and inhibitory neurotransmission and cerebral energy metabolism.

Besides the detection of steady-state metabolite concentrations, NMR also offers the possibility of measuring absolute fluxes through important metabolic pathways, like the tricarboxylic acid (TCA) cycle. Following the infusion of [¹³C]-enriched-glucose (or acetate), NMR allows the dynamic detection of a range of [¹³C]-enriched metabolites. The formation of [4-¹³C]-glutamate (which is in rapid exchange with [4-¹³C]-a-ketoglutarate) is indicative of the neuronal TCA cycle flux in glutamatergic neurons, while the formation of [4-¹³C]-GABA gives flux information on GABAergic neurons. The subsequent formation of [4-¹³C]-glutamine is explained by a glutamate/glutamine neurotransmitter cycle between neurons and astrocytes. Using metabolic modeling, as developed by Yale MRRC, the data can be converted into quantitative fluxes of metabolic pathways involved in brain energy metabolism and neurotransmission.

Researchers:
Douglas L. Rothman
Graeme F. Mason
Robin A. de Graaf
Kitt F. Petersen
Gerald I. Shulman
Ognen A. C. Petroff
Edward J. Novotny