A mathematical model of compartmentalized neurotransmitter metabolism in the human brain

Abstract

Gruetter, Rolf, Elizabeth R. Seaquist, and Kâ mil Ugurbil. A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. Am J Physiol Endocrinol Metab 281: E100-E112, 2001.-After administration of enriched [1-13 C]glucose, the rate of 13 C 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 13 C 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 Ϯ 0.06 mol ⅐ g Ϫ1 ⅐ min Ϫ1 , was comparable to the exchange rate between (mitochondrial) 2-oxoglutarate and (cytosolic) glutamate (V x , 0.57 Ϯ 0.19 mol ⅐ g Ϫ1 ⅐ min Ϫ1 ), which may reflect to a large extent malate-aspartate shuttle activity. At rest, oxidative glucose consumption [CMR Glc(ox) ] was 0.41 Ϯ 0.03 mol ⅐ g Ϫ1 ⅐ min Ϫ1 , and (glial) pyruvate carboxylation (V PC ) was 0.09 Ϯ 0.02 mol ⅐ g Ϫ1 ⅐ min Ϫ1. The flux through glutamine synthetase (V syn ) was 0.26 Ϯ 0.06 mol ⅐ g Ϫ1 ⅐ min Ϫ1 . A fraction of V syn was attributed to be from (neuronal) glutamate, and the corresponding rate of apparent glutamatergic neurotransmission (V NT ) was 0.17 Ϯ 0.05The ratio [V NT /CMR Glc(ox) ] was 0.41 Ϯ 0.14 and thus clearly different from a 1:1 stoichiometry, consistent with a significant fraction (ϳ90%) of ATP generated in astrocytes being oxidative. The study underlines the importance of assumptions made in modeling 13 C labeling data in brain.nuclear magnetic resonance; glutamate; neurotransmission; in vivo spectroscopy IN THE TRADITIONAL CONTEXT of neuroscience, the brain's tasks are mainly accomplished by the neurons, with the surrounding glial cells performing simple, passive tasks of maintaining the milieu required for optimal neurotransmission. However, the glial cells are more than just passive components in neuronal function, in that they are intimately involved in the process of neurotransmission through glial uptake of glutamate (Glu) from the synaptic cleft (64,77,78). Glu is the major excitatory neurotransmitter (62); it is present in the mammalian brain in high concentrations and is dynamically stored in presynaptic vesicles (73). Despite the high intracellular concentration of Glu, the extracellular concentration must be maintained very low (ϳ0.004 mM) to avoid excitotoxicity. Presynaptic release of Glu into the synaptic cleft therefore requires efficient uptake mechanisms, which are achieved by Glu transporters (2). Most of the metabolic evidence suggests that uptake by glia is the most important process. Most of the Glu is in neurons (51), as is most of the glutaminase activity (52), whereas astrocytes contain most of the glutamine (Gln) (51), all of the glutamine synthetase (42), and pyruvate carboxylase (63); they predominantly take up and metabolize acetate (74). Early studies showed that cerebral Glu metabolism is compartmentalized, involving two major metabolic po...

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

“…Using this labeling pattern for modeling, rates of pyruvate carboxylation corresponding to B10% of total pyruvate metabolism in brain (Table 1) have consistently been demonstrated in both animal and human brain (Aureli et al, 1997;Gruetter et al, 2001;Ö z et al, 2004). Sizeable rates of pyruvate carboxylation have also been determined in rabbit brain, using a different NMR-based approach (Lapidot and Gopher, 1994).…”

“…However, direct comparison of relative rates of glucose and lactate oxidation are difficult to interpret because of the metabolic consequences of administering 'loading' (versus tracer) doses of labeled lactate and the many metabolic steps and metabolite pools between the labeled precursor and metabolites that must be analyzed to draw firm conclusions. Waagepetersen et al (1998) concluded that lactate is less efficient The expected precursor-product relationship (larger isotope enrichment in the precursor than in the product) is observed, since labeling of C4 in glutamine is secondary to [4-13 C]glutamate uptake by astrocytes and glutamine formation in these cells (from Gruetter et al, 2001). (B) [2-13 C]Acetate leads to an increase in glutamine labeling in C4 (filled circles), primarily due to net synthesis of glutamine in astrocytes, which with a normal precursor-product relationship is followed by slower labeling of C4 in glutamate (open squares), secondary to glutamine uptake by neurons and its conversion to glutamate (From Lebon et al, 2002).…”

Modeling of Brain Metabolism and Pyruvate Compartmentation Using 13C NMR in Vivo: Caution Required

“…The transaminase-catalyzed exchange between amino acids and a-keto acids in the cycle (aspartate and oxaloacetate, glutamate, and a-ketoglutarate) and its transport across the mitochondrial membrane is assumed to be equal in both cell compartments (Vx). Because it has been noted in previous studies that the carbon entering oxaloacetate from pyruvate may not be fully randomized by exchange with fumarate, the parameter Vf' 16,17 was explicitly included but with these data sets the result was always a very small value (not reported).…”

Brain Glycogen Content and Metabolism in Subjects with Type 1 Diabetes and Hypoglycemia Unawareness

“…This blood glucose target was chosen to minimize dilution of infused 13 C-labeled glucose and maintain high IE levels in blood glucose and also because label incorporation into brain glycogen primarily occurs through turnover, rather than net synthesis, at such slight hyperglycemic conditions (Ö z et al, 2007). Additional blood samples were frozen for the later determination of plasma insulin concentrations by a chemiluminescent assay (Immulite, Diagnostic Products Corporation, Los Angeles, CA, USA), and of the IE of the plasma glucose by gas chromatography-mass spectroscopy as described previously (Gruetter et al, 2001). The infusion of 13 C-glucose continued for 32 ± 2 hours and then switched to unlabeled glucose for another 19±2 hours ( Figure 1).…”

“…Thus, the fitted variables were total glycogen concentration [Glyc] and turnover rate V syn = V phos . The cerebral metabolic rate of glucose (CMR glc ) in the human brain was assumed to be 0.4 mmol/g/min = 24 mmol/g/h (Gruetter et al, 2001) and the glucose-6-phosphate concentration 0.1 mmol/g (Watanabe and Passonneau, 1973). As a primary analysis, the model was fitted to data obtained from each individual subject.…”