Figure 1.

Cartoon of glucose metabolism via pyruvate in neurons (left—N) and astrocytes (right—A) and of glutamine-glutamate (γ-aminobutyric acid, GABA) cycling. This figure shows (i) metabolic pathways; (ii) metabolic rates (µmol/min per 100 mg protein or 1 g wet wt); and (iii) inhibition by excess extracellular glutamate or glutamine. One molecule of glucose is metabolized by glycolysis in the cytosol to two molecules of pyruvate in a complex and strictly regulated pathway (not shown). In both neurons and astrocytes pyruvate metabolism via acetyl coenzyme A (ac.CoA) leads to formation of citrate in the tricarboxylic acid (TCA) cycle by condensation with preexisting oxaloacetate (OAA), an end result of the previous turn of the cycle. Citrate oxidation in the TCA cycle includes two decarboxylations, resulting in re-formation of oxaloacetate, ready for another turn of the cycle, and reduction of NAD⁺ to NADH (and a single FAD to FADH₂), leading to large amounts of energy (ATP) via re-oxidation in the electron transport chain. Pyruvate carboxylation, which is active in astrocytes, but not in neurons, creates a new molecule of oxaloacetate, which after condensation with acetyl coenzyme A, forms citrate that is metabolized in the TCA cycle to α-ketoglutarate (α-KG), which can leave the cycle to form glutamate (glu), catalyzed by aspartate aminotransferase (AAT). Further metabolism by the cytosolic and astrocyte-specific enzyme glutamine synthetase leads to the formation of glutamine (gln), which after transport to neurons is converted to transmitter glutamate or GABA in complex reactions (reviewed in [6]). Released transmitter glutamate is almost quantitatively re-accumulated in astrocytes, together with at least part of the released GABA (upper line of glu-gln cycle) and re-accumulated in the astrocytic cytosol. Here, 75%–80% is converted to glutamine and re-enters the glutamine-glutamate (GABA) cycle. The remaining 20%–25% is oxidatively degraded. This paper suggests that the default mechanism for the initial conversion of glutamate to α-KG is also transamination by AAT (see Figure 3), but it does not exclude a minor contribution by glutamate dehydrogenase (GDH). Operation of AAT in two opposite directions is thermodynamically possible since the reactions take place in two different compartments (cytosol and mitochondria) and also are temporally separate. α-KG is metabolized via malate, which can exit to the cytosol and be decarboxylated by cytosolic malic enzyme to pyruvate, which is oxidized in the TCA cycle via acetyl coenzyme A. Another possibility is that malate does not exit the TCA cycle but is further metabolized to α-KG after condensation with acetyl coenzyme A, allowing re-synthesis of another molecule of glutamate from only one molecule of pyruvate [6]. The degraded glutamate/GABA must in the long term be replaced by a quantitatively similar production of glutamate from glucose, in the first case by complete de novo synthesis from one molecule glucose, in the second from one half of a glucose molecule. However, temporary fluctuations in the content of glutamate occur. The initial part of GABA metabolism is different, as all GABA is metabolized via succinic semialdehyde, succinate and α-KG to glutamate. Numbers in black show rates re-calculated as µmol/min per 100 mg protein based on rate of glucose uptake in our own cultured astrocytes, and those in red are in vivo rates from [10]. The percentage distribution between metabolism via pyruvate carboxylation and acetyl coenzyme A is based on averages of results tabulated in [12]. Those for glutamate metabolism to either α-KG or glutamine are from [10]. The in vivo results that 40% of 0.8 µmol/min per 100 mg protein is metabolized via pyruvate carboxylation is consistent with the pyruvate carboxylation rates found by Kaufman and Driscoll [13] and overall the correlation between the metabolic rates in vivo and in culture is remarkably good, although other authors have described lower rates of glucose metabolism in cultured astrocytes. It should also be kept in mind that lightly anaesthetized mice have been used in most in vivo studies. Blue arrows: Suggested prevention of glutamate formation from α-KG and accompanying aspartate utilization by the presence of high extracellular concentrations of glutamate or glutamine, with the consequence that the AAT-mediated, coupled glutamate formation and degradation illustrated in Figure 3 can no longer operate. This appears to be the reason that so many studies have concluded that glutamate oxidation is catalyzed by GDH, whereas studies using low glutamate/glutamine concentrations find that AAT is involved. Modified from [6].