A mathematical model of compartmentalized neurotransmitter metabolism in the human brain

After administration of enriched [1-C-13] glucose, the rate of C-13 label incorporation into glutamate C4, C3, and C2, glutamine C4, C3, and C2, and aspartate C2 and C3 was simultaneously measured in six normal subjects by C-13 NMR at 4 Tesla in 45-ml volumes encompassing the visual cortex. The resulting eight time courses were simultaneously fitted to a mathematical model. The rate of (neuronal) tricarboxylic acid cycle flux (V-PDH), 0.57 +/- 0.06 mu mol.g(-1).min(-1), was comparable to the exchange rate between (mitochondrial) 2-oxoglutarate and (cytosolic) glutamate (V-x, 0.57 +/- 0.19 mu mol.g(-1).min(-1)), which may reflect to a large extent malate-aspartate shuttle activity. At rest, oxidative glucose consumption [CMRGlc(ox)] was 0.41 +/- 0.03 mu mol.g(-1).min(-1), and (glial) pyruvate carboxylation (V-PC) was 0.09 +/- 0.02 mu mol.g(-1).min(-1). The flux through glutamine synthetase (V-syn) was 0.26 +/- 0.06 mu mol.g(-1).min(-1). A fraction of Vsyn was attributed to be from (neuronal) glutamate, and the corresponding rate of apparent glutamatergic neurotransmission (V-NT) was 0.17 +/- 0.05 mu mol.g(-1).min(-1). The ratio [V-NT/CMRGlc(ox)] was 0.41 +/- 0.14 and thus clearly different from a 1:1 stoichiometry, consistent with a significant fraction (similar to 90%) of ATP generated in astrocytes being oxidative. The study underlines the importance of assumptions made in modeling C-13 labeling data in brain.