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 i ncorporation into glutamate C4, C3, and C2, glutamine C4, C3, and C2, and a spartate 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 resu lting 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 (mitoc hondrial) 2-oxoglutarate and (cytosolic) glutamate (V-x, 0.57 +/- 0.19 mu m ol.g(-1).min(-1)), which may reflect to a large extent malate-aspartate shu ttle 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) w as 0.09 +/- 0.02 mu mol.g(-1).min(-1). The flux through glutamine synthetas e (V-syn) was 0.26 +/- 0.06 mu mol.g(-1).min(-1). A fraction of Vsyn was at tributed to be from (neuronal) glutamate, and the corresponding rate of app arent 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 di fferent from a 1:1 stoichiometry, consistent with a significant fraction (s imilar to 90%) of ATP generated in astrocytes being oxidative. The study un derlines the importance of assumptions made in modeling C-13 labeling data in brain.