Abstract
Anaplerosis, or de novo formation of intermediates of the tricarboxylic acid (TCA) cycle, compensates for losses of TCA cycle intermediates, especially α-ketoglutarate, from brain cells. Loss of α-ketoglutarate occurs through release of glutamate and GABA from neurons and through export of glutamine from glia, because these amino acids are α-ketoglutarate derivatives. Anaplerosis in the brain may involve four different carboxylating enzymes: malic enzyme, phosphoenopyruvate carboxykinase (PEPCK), propionyl-CoA carboxylase, and pyruvate carboxylase. Anaplerotic carboxylation was for many years thought to occur only in glia through pyruvate carboxylase; therefore, loss of transmitter glutamate and GABA from neurons was thought to be compensated by uptake of glutamine from glia. Recently, however, anaplerotic pyruvate carboxylation was demonstrated in glutamatergic neurons, meaning that these neurons to some extent can maintain transmitter synthesis independently of glutamine. Malic enzyme, which may carboxylate pyruvate, was recently detected in neurons. The available data suggest that neuronal and glial pyruvate carboxylation could operate at as much as 30% and 40–60% of the TCA cycle rate, respectively. Cerebral carboxylation reactions are probably balanced by decarboxylation reactions, because cerebral CO2 formation equals O2 consumption. The finding of pyruvate carboxylation in neurons entails a major revision of the concept of the glutamine cycle.
Similar content being viewed by others
References
Hassel B. and Bråthe A. (2000) Neuronal pyruvate carboxylation supports formation of transmitter glutamate. J. Neurosci. 20, 1342–1347.
Hassel B. and Bråthe A. (2000) Cerebral metabolism of lactate in vivo. Evidence for neuronal pyruvate carboxylation. J. Cereb. Blood Flow Metab. 20, 327–336.
Vogel R., Jennemann G., Seitz J., Wiesinger H., and Hamprecht B. (1998) Mitochondrial malic enzyme: purification from bovine brain, generation of an antiserum, and immunocyto-chemical localization in neurons of rat brain. J. Neurochem. 71, 844–852.
Cruz F., Scott S. R., Barroso I., Santisteban P., and Cerdan S. (1998) Ontogeny and cellular localization of the pyruvate recycling system in rat brain. J. Neurochem. 70, 2613–2619.
McKenna M. C., Stevenson J. H., Huang X., Tildon J. T., Zielke C. L., and Hopkins I. B. (2000) Mitochondrial malic enzyme activity is much higher in mitochondria from cortical synaptic terminals compared with mitochondria from primary cultures of cortical neurons or cerebellar granule cells. Neurochem. Int. 36, 451–459.
Hertz L., Dringen R., Schousboe A., and Robinson S. R. (1999) Astrocytes: glutamate producers for neurons. J. Neurosci. Res. 57, 417–428.
Daikhin Y. and, Yudkoff M. (2000) Compartmentation of brain glutamate metabolism in neurons and glia. J. Nutr. 130 (Suppl), 1026S-1031S.
Sokoloff L. (1989) Circulation and energy metabolism of the brain, in Basic Neurochemistry, 4th ed. (Siegel G., Agranoff B., Albers R. W., and Molinoff P., eds.), Raven Press, New York, pp. 565–590.
Miller L. P., Pardridge W. M., Braun L. D., and Oldendorf W. H. (1985) Kinetic constants for blood-brain barrier amino acid transport in conscious rats. J. Neurochem. 45, 1427–1432.
Braun L. D., Miller L. P., Pardridge W. M., and Oldendorf W. H. (1985) Kinetics of regional blood-brain barrier glucose transport and cerebral blood flow determined with the carotid injection technique in conscious rats. J. Neurochem. 44, 911–915.
Life Technologies (1998) 1998/1999 Catalogue for GIBCOBRL Cell Culture products, pp. 2-46–2-47.
Patel A. J. and Hunt A. (1985) Concentration of free amino acids in primary cultures of neurones and astrocytes. J. Neurochem. 44, 1816–1821.
Hassel B., Sonnewald U., Unsgard G., and Fonnum F. (1994) NMR spectroscopy of cultured astrocytes: effects of glutamine and the gliotoxin fluorocitrate. J. Neurochem. 62, 2187–2194.
Crane R. K. and Ball E. G. (1951) Relationship of 14CO2 fixation to carbohydrate metabolism in retina. J. Biol. Chem. 189, 269–276.
Moldave K., Winzler R. J., and Pearson H. E. (1953) The incorporation in vitro of C14 into amino acids of control and virus-infected mouse brain. J. Biol. Chem. 200, 357–365.
Cheng S.-C. (1971) CO2 fixation in the nervous tissue, in International Review of Neurobiology, vol. 14 (Pfeiffer C. C. and Smythies J. R., eds.), Academic Press, New York, pp. 125–157.
Kurz G. M., Wiesinger H., and Hamprecht B. (1993) Purification of cytosolic malic enzyme from bovine brain, generation of monoclonal antibodies, and immunocytochemical localization of the enzyme in glial cells of neural primary cultures. J. Neurochem. 60, 1467–1474.
McKenna M. C., Tildon J. T., Stevenson J. H., Huang X., and Kingwell K. G. (1995) Regulation of mitochondrial and cytosolic malic enzymes from cultured rat brain astrocytes. Neurochem. Res. 12, 1491–501.
Russell R. R. III, and Taegtmeyer H. (1991) Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am. J. Physiol. 261, H1756-H1762.
Shank R. P., Campbell G. L., Freytag S. O., and Utter M. F. (1981) Evidence that pyruvate carboxylase is an astrocyte specific enzyme in CNS tissues. Abstr. Soc. Neurosci. 7, 936.
Shank R. P., Bennett G. S., Freytag S. O., and Campbell G. L. (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res. 329, 364–367.
Yu A. C. H., Drejer J., Hertz L., and Schousboe A. (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J. Neurochem. 41, 1484–1487.
Cesar M. and Hamprecht B. (1995) Immunocytochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase. J. Neurochem. 64, 2312–2318.
Cheng S.-C. and Cheng R. H. (1972) A mitochondrial phosphoenolpyruvate carboxykinase from rat brain. Arch. Biochem. Biophys. 151, 501–511.
Patel M. S. (1974) The relative significance of CO2-fixing enzymes in the metabolism of rat brain. J. Neurochem. 22, 717–724.
Wiese T. J., Lambeth D. O., and Ray P. D. (1991) The intracellular distribution and activities of phosphoenolpyruvate carboxykinase isozymes in various tissues of several mammals and birds. Comp. Biochem. Physiol. B 100, 297–302.
Schmoll D., Fuhrmann E., Gebhardt R., and Hamprecht B. (1995) Significant amounts of glycogen are synthesized from 3-carbon compounds in astroglial primary cultures from mice with participation of the mitochondrial phosphoenolpyruvate carboxykinase isoenzyme. Eur. J. Biochem. 227, 308–315.
Rognstad R. (1982) 14CO2 fixation by phosphoenolpyruvate carboxykinase during glyconeogenesis in the intact rat liver cell. J. Biol. Chem. 257, 11,486–11,488.
Lane M. D., Chang H. C., and Miller R. S. (1969) Phosphoenolpyruvate carboxykinase from pig liver mitochondria, in Methods in Enzymology, vol. 13 (Lowenstein J. M., ed.), Academic Press, New York, pp. 270–277.
Kusakabe T., Maeda M., Hoshi N., Sugino T., Watanabe K., Fukuda T., and Suzuki T. (2000) Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J. Histochem. Cytochem. 48, 613–622.
Cammer W. (1991) Immunostaining of carbamoylphosphate synthase II and fatty acid synthase in glial cells in rat, mouse, and hamster brains suggests roles for carbonic anhydrase in biosynthetic processes. Neurosci. Lett. 129, 247–250.
Cammer W. and Downing M. (1991) Localization of the multifunctional protein CAD in astrocytes of rodent brain. J. Histochem. Cytochem. 39, 695–700.
Sun D., Swaffield J. C., Johnston S. A., Milligan C. E., Zoeller R. T., and Schwartz L. M. (1997) Identification of a phylogenetically conserved Sug1 CAD family member that is differentially expressed in the mouse nervous system. J. Neurobiol. 33, 877–890.
Appel S. H. and Silverberg D. H. (1968) Pyrimidine synthesis in tissue culture. J. Neurochem. 15, 1437–1443.
Allsop J. and Watts R. W. (1983) Purine de novo synthesis in liver and developing rat brain, and the effect of some inhibitors of purine nucleotide interconversion. Enzyme 30, 172–180.
Pardridge W. M. and Oldendorf W. H. (1977) Transport of metabolic substrates through the blood-brain barrier. J. Neurochem. 28, 5–12.
Lahoya J. L., Benavides J., and Ugarte M. (1980) Glycine metabolism and glycine synthase activity during the postnatal development of rat brain. Dev. Neurosci. 3, 75–80.
Sato K., Yoshida S., Fujiwara K., Tada K., and Tohyama M. (1991) Glycine cleavage system in astrocytes. Brain Res. 567, 64–70.
Cheng S.-C. and Nakamura R. (1972) Metabolism related to the tricarboxylic acid cycle in rat brain slices. Observations on CO2 fixation and metabolic compartmentation. Brain Res. 38, 355–370.
Salganicoff L. and Koeppe R. E. (1968) Subcellular distribution ot pyruvate carboxylase, diphosphopyridine nucleotide and triphosphopyridine nucleotide isocitrate dehydrogenases, and malate enzyme in rat brain. J. Biol. Chem. 243, 3416–3420.
Wolever T. M., Josse R. G., Leiter L. A., and Chiasson J. L. (1997) Time of day and glucose tolerance status affect serum short-chain fatty acid concentrations in humans. Metabolism 46, 805–811.
Suchy S. F. and Wolf B. (1986) Effect of biotin deficiency and supplementation on lipid metabolism in rats: cholesterol and lipoproteins. Am. J. Clin. Nutr. 43, 831–838.
Rodriguez-Pombo P., Sweetman L., and Ugarte M. (1992) Primary cultures of astrocytes from rat as a model for biotin deficiency in nervous tissue. Mol. Chem. Neuropathol. 16, 33–44.
Murthy C. R. and Hertz L. (1987) Acute effect of ammonia on branched-chain amino acid oxidation and incorporation into proteins in astrocytes and in neurons in primary cultures. J. Neurochem. 49, 735–741.
Bixel M. G. and Hamprecht B. (2000) Immunocytochemical localization of beta-methyl-crotonyl-CoA carboxylase in astroglial cells and neurons in culture. J. Neurochem. 74, 1059–1067.
Buniatian H. C. and Davtian M. A. (1966) Urea synthesis in brain. J. Neurochem. 13, 743–753.
Braissant O., Gotoh T., Loup M., Mori M., and Bachmann C. (1999) L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study. Brain. Res. Mol. Brain Res. 70, 231–241.
Furie B., Bouchard B. A., and Furie B. C. (1999) Vitamin K-dependent biosynthesis of γ-carboxyglutamic acid. Blood 93, 1798–1808.
Stenflo J., Ferlund P., Egan W., and Roepstorff P. (1974) Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc. Natl. Acad. Sci. USA 71, 2730–2733.
Price P. A. and Williamson M. K. (1985) Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein. J. Biol. Chem. 260, 14971–14975.
Manfioletti G., Brancolini C., Avanzi G., and Schneider C. (1993) The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol. Cell. Biochem. 13, 4976.
Nakano T., Kawamoto K., Kishino J., Nomura K., Higashino K., and Arita H. (1997) Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells. Biochem. J. 323, 387–392.
de Boer-van den Berg M. A., Thijssen H. H., and Vermeer C. (1986) The in vivo effects of acenocoumarol, phenprocoumon and warfarin on vitamin K epoxide reductase and vitamin K-dependent carboxylase in various tissues of the rat. Biochim. Biophys. Acta 884, 150–157.
Prieto A. L., Weber J. L., Tracy S., Heeb M. J., and Lai C. (1999) Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system. Brain Res. 816, 646–661.
Kulman J. D., Harris J. E., Haldeman B. A., and Davie E. W. (1997) Primary structure and tissue distribution of two novel proline-rich gamma-carboxyglutamic acid proteins. Proc. Natl. Acad. Sci. USA 94, 9058–9062.
Pati S. and Helmbrecht G. D. (1994) Congenital schizencephaly associated with in utero warfarin exposure. Reprod. Toxicol. 8, 115–120.
Brown M. A., Stenberg L. M., Persson U., and Stenflo J. (2000) Identification and purification of vitamin K-dependent proteins and peptides with monoclonal antibodies specific for gamma -carboxyglutamyl (Gla) residues. J. Biol. Chem. 275, 19,795–19,802.
Waelsch H., Berl S., Rossi C. A., Clarke D. D., and Purpura D. P. (1964) Quantitative aspects of CO2 fixation in mammalian brain in vivo. J. Neurochem. 11, 717–728.
Henn F. A., Goldstein M. N., and Hamberger A. (1974) Uptake of the neurotransmitter candidate glutamate by glia. Nature 249, 663–664.
Divac I., Fonnum F., and Storm-Mathisen J. (1977) High affinity uptake of glutamate in terminals of corticostriatal axons. Nature 266, 377–378.
Haugeto O., Ullensvang K., Levy L. M., Chaudhry F. A., Honoré T., Nielsen M., et al. (1996) Brain glutamate transporter proteins form homomultimers. J. Biol. Chem. 271, 27,715–27,722.
Guastella J., Nelson N., Nelson H., Czyzyk L., Keynan S., Miedel M. C., et al. (1990) Cloning and expression of a rat brain GABA transporter. Science 249, 1303–1306.
Radian R., Ottersen O. P., Storm-Mathisen J., Castel M., and Kanner B. I. (1990) Immunocytochemical localization of the GABA transporter in rat brain. J. Neurosci. 10, 1319–1330.
Balázs R., Machiyama Y., Hammond B. J., Julian T., and Richter D. (1970) The operation of the gamma-aminobutyrate bypath of the tricarboxylic acid cycle in brain tissue in vitro. Biochem. J. 116, 445–461.
Hassel B., Paulsen R. E., Johnsen A., and Fonnum F. (1992) Selective inhibition of glial cell metabolism in vivo by fluorocitrate. Brain Res. 576, 120–124.
Hassel B., Sonnewald U., and Fonnum F. (1995) Glial-neuronal interactions as studied by cerebral metabolism of [2-13C]acetate and [1-13C]glucose. An ex vivo 13C NMR spectroscopic study. J. Neurochem. 64, 2773–2782.
Berl S., Takagaki G., Clarke D. D., and Waelsch H. (1962) Metabolic compartments in vivo. J. Biol. Chem. 237, 2562–2569.
Lee W. J., Hawkins R. A., Vina J. R., and Peterson D. R. (1998) Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal. Am. J. Physiol. 274, C1101-C1107.
Grill V., Bjorkman O., Gutniak M., and Lindqvist M. (1992) Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release fornitrogen balance. Metabolism 41, 28–32.
Bradford H. F., Ward H. K., and Thomas A. J. (1978) Glutamine: a major substrate for nerve endings. J. Neurochem. 30, 1453–1460.
Zielke H. R., Collins R. M., Jr., Baab P. J., Huang Y., Zielke C. L., and Tildon J. T. (1998) Compartmentation of [14C]glutamate and [14C]glutamine oxidative metabolism in the rat hippocampus as determined by microdialysis. J. Neurochem. 71, 1315–1320.
Cotman C. W. and Hamberger A. C. (1978) Glutamate as a CNS neurotransmitter: properties of release, inactivation and biosynthesis, in Amino Acids as Chemical Transmitters (Fonnum F., ed.), Plenum Press, New York, pp. 379–412.
Hamberger A. C., Chiang G. H., Nylén E. S., Scheff S. W., and Cotman C. W. (1979) Glutamate as a CNS transmitter. I. Evaluation of glucose and glutamine as precursors for the synthesis of the preferentially released glutamate. Brain Res. 168, 513–530.
Tapia R. and Gonzalez M. (1978) Glutamine and glutamate as precursors of the releasable pool of GABA in brain cortex slices. Neurosci. Lett. 10, 165–169.
Hassel B., Bachelard H. S., Jones P., Fonnum F., and Sonnewald U. (1997) Trafficking of amino acids between neurons and glia in vivo. Effects of inhibition of glial meabolism by fluoroacetate. J. Cereb. Blood Flow Metab. 17, 1230–1238.
Sonnewald U., Westergaard N., Krane J., Unsgard G., Petersen S. B., and Schousboe A. (1991) First direct demonstration of preferential release of citrate from astrocytes using [13C]NMR spectroscopy of cultured neurons and astrocytes. Neurosci. Lett. 128, 235–239.
Westergaard N., Sonnewald U., Unsgard G., Peng L., Hertz L., and Schousboe A. (1994) Uptake, release, and metabolism of citrate in neurons and astrocytes in primary cultures. J. Neurochem. 62, 1727–1733.
Hassel B., Westergaard N., Schousboe A., and Fonnum F. (1995) Metabolic differences between primary cultures of astrocytes and neurons from cerebellum and cerebral cortex. Effects of fluorocitrate. Neurochem. Res. 20, 413–420.
Gatfield P. D., Lowry O. H., Schulz D. W., and Passonneau J. V. (1996) Regional energy reserves in mouse brain and changes with ischaemia and anaesthesia. J. Neurochem. 13, 185–195.
Martinez-Hernandez A., Bell K. P., and Norenberg M. D. (1977) Glutamine synthetase: glial localization in brain. Science 195, 1356–1358.
Tansey F. A., Farooq M., and Cammer W. (1991) Glutamine synthetase in oligodendrocytes and astrocytes: new biochemical and immunocytochemical evidence. J. Neurochem. 56, 266–272.
Sonnewald U., Westergaard N., Petersen S. B., Unsgard G., and Schousboe A. (1993) Metabolism of [U-13C]glutamate in astrocytes studied by 13C NMRspectroscopy: incorporation of more label into lactate than into glutamine demonstrates the importance of the tricarboxylic acid cycle. J. Neurochem. 61, 1179–1182.
McKenna M. C., Sonnewald U., Huang X., Stevenson J., and Zielke H. R. (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J. Neurochem. 66, 386–393.
Hertz L. (1979) Functional interactions between neurons and astrocytes. I. Turnover and metabolism of putative amino acid transmitters. Prog. Neurobiol. 13, 277–323.
Thanki C. M., Sugden D., Thomas N. J., and Bradford H. F. (1983) In vivo release from cerebral cortex of [14C]glutamate synthesized from [U-14C]glutamine. J. Neurochem. 41, 611–617.
Fonnum F. (1991) Neurochemical studies on glutamate-mediated neurotransmission, in Excitatory Amino Acids, FIDIA Research Foundation Symposium Series, vol. 5 (Meldrum B. S., Moroni F., Simon R. P., and Woods J. H., eds.), Raven Press, New York, pp. 15–25.
Najlerahim A., Harrison P. J., Barton A. J., Heffernan J., and Pearson R. C. (1990) Distribution of messenger RNAs encoding the enzymes glutaminase, aspartate aminotransferase and glutamic acid decarboxylase in rat brain. Brain Res. Mol. Brain Res. 7, 317–333.
Kaneko T. and Mizuno N. (1994) Glutamate-synthesizing enzymes in GABAergic neurons of the neocortex: a double immunofluorescence study in the rat. Neuroscience 61, 839–849.
Ottersen O. P., Takumi Y., Matsubara A., Landsend A. S., Laake J. H. and Usami S. (1998) Molecular organization of a type of peripheral glutamate synapse: the afferent synapses of hair cells in the inner ear. Prog. Neurobiol. 54, 127–148.
Laake J. H., Takumi Y., Eidet J., Torgner I. A., Roberg B., Kvamme E., and Ottersen O. P. (1999) Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum. Neuroscience 88, 1137–1151.
Van den Berg C. J. (1973) A model of compartmentataion in mouse brain based on glucose and acetate metabolism, in Metabolic Compartmentation in the Brain (Balazs R. and Cremer J. E., eds.), MacMillan, London, pp. 137–166.
Nicklas W. J. and Clarke D. D. (1969) Decarboxylation studies of glutamate, glutamine, and aspartate from brain labelled with [1-14C]acetate, L-[U-14C]-aspartate, and L-[U-14C]glutamate. J. Neurochem. 16, 549–558.
Clarke D. D. and Berl S. (1973) Alteration in the expression of compartmentation: in vitro studies, in Metabolic Compartmentation in the Brain (Balazs R., and Cremer J. E., eds.), MacMillan, London, pp. 97–106.
Hassel B. and Sonnewald U. (1995) Glial formation of pyruvate and lactate from TCA cycle intermediates. Implications for the inactivation of transmitter amino acids? J. Neurochem. 65, 2227–2234.
Cerdan S., Kunnecke B., and Seelig J. (1990) Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. J. Biol. Chem. 265, 12,916–12,926.
O’Neal R. M. and Koeppe R. E. (1966) Precursors in vivo of glutamate, aspartate and their derivatives of rat brain. J. Neurochem. 13, 835–847.
Bakken I. J., Sonnewald U., Clark J. B., and Bates T. E. (1997) [U-13C]glutamate metabolism in rat brain mitochondria reveals malic enzyme activity. Neuroreport 8, 1567–1570.
Bakken I. J., White L. R., Aasly J., Unsgard G., and Sonnewald U. (1997) Lactate formation from [U-13C]aspartate in cultured astrocytes: compartmentation of pyruvate metabolism. Neurosci. Lett. 237, 117–120.
Bouzier A. K., Thiaudiere E., Biran M., Rouland R., Canioni P., and Merle M. (2000) The metabolism of [3-13C]lactate in the rat brain is specific of a pyruvate carboxylase-deprived compartment. J. Neurochem. 75, 480–486.
Merle M., Martin M., Villegier A., and Canioni P. (1996) [1-13C]glucose metabolism in brain cells: isotopomer analysis of glutamine from cerebellar astroyctes and glutamate from granule cells. Dev. Neurosci. 18, 460–468.
Shank R. P., Leo G. C., and Zielke H. R. (1993) Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance analysis of D-[1-13C]glucose metabolism. J. Neurochem. 61, 315–323.
Lapidot A. and Gopher A. (1994) Cerebral metabolic compartmentation. Estimation of glucose flux via pyruvate carboxylase/pyruvate dehydrogenase by 13C NMR isotopomer analysis of D-[U-13C]glucose metabolites. J. Biol. Chem. 269, 27,198–27,208.
Aureli T., Di Cocco M. E., Calvani M., and Conti F. (1997) The entry of [1-13C]glucose into biochemical pathways reveals a complex compartmentation and metabolite trafficking between glia and neurons: a study by 13C-NMR spectroscopy. Brain Res. 765, 218–227.
Waniewski R. A. and Martin D. L. (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J. Neurosci. 18, 5225–5233.
Cheng S.-C., Naruse H., and Brunner E. A. (1978) Effects of sodium thiopental on the tricarboxylic acid cycle metabolism in mouse brain: CO2 fixation and metabolic compartmentation. J. Neurochem. 30, 1591–1593.
Berl S., Takagaki G., Clark D. D., and Waelsch H. (1962) Carbon dioxide fixation in the brain. J. Biol. Chem. 237, 2570–2573.
Hassel B., Johannessen C. U., Sonnewald U., and Fonnum F. (1998) Quantification of the GABA shunt and the importance of the GABA shunt versus the 2-oxoglutarate dehydrogenase pathway in GABAergic neurons. J. Neurochem. 71, 1511–1518.
Mason G. F., Rothman D. L., Behar K. L., and Shulman R. G. (1992) NMR determination of the TCA cycle rate and alpha-2ketoglutarate/glutamate exchange rate in rat brain. J. Cereb. Blood Flow Metab. 12, 434–447.
Mason G. F., Gruetter R., Rothman D. L., Behar K. L., Shulman R. G., and Novotny E. J. (1995) Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR. J. Cereb. Blood Flow Metab. 15, 12–25.
Fitzpatrick S. M., Hetherington H. P., Behar K. L., and Shulman R. G. (1990) The flux from glucose to glutamate in the rat brain in vivo as determined by 1H-observed, 13C-edited NMR spectroscopy. J. Cereb. Blood Flow Metab. 10, 170–179.
Miller A. K., Alston R. L., and Corsellis J. A. (1980) Variation with age in the volumes of grey and white matter in the cerebral hemispheres of man: measurements with an image analyser. Neuropathol. Appl. Neurobiol. 6, 119–132.
Robins E., Smith D. E., Eydt K. M., and McCaman R. E. (1956) The quantitative histochemistry of the cerebral cortex-II. Architectonic distribution of nine enzymes in the motor and visual cortices. J. Neurochem. 1, 68–76.
Mason G. F., Pan J. W., Chu W. J., Newcomer B. R., Zhang Y., Orr R., and Hetherington H. P. (1999) Measurement of the tricarboxylic acid cycle rate in human grey and white matter in vivo by H-[13C] magnetic resonance spectroscopy at 4.1 T. J. Cereb. Blood Flow Metab. 19, 1179–1188.
Pardridge W. M. (1983) Brain metabolism: a perspective from the blood-brain barrier. Physiol. Rev. 63, 1481–1535.
Westergaard N., Varming T., Peng L., Sonnewald U., Hertz L., and Schousboe A. (1993) Uptake, release, and metabolism of alanine in neurons and astrocytes in primary cultures. J. Neurosci. Res. 35, 540–545.
Erecinska M., Nelson D., Nissim I., Daikhin Y., and Yudkoff M. (1994) Cerebral alanine transport and alanine aminotransferase reaction: alanine as a source of neuronal glutamate. J. Neurochem. 62, 1953–1964.
Hutson S. M., Berkich D., Drown P., Xu B., Aschner M., and LaNoue K. F. (1998) Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J. Neurochem. 71, 863–874.
McKenna M. C., Stevenson J. H., Huang X., and Hopkins I. B. (2000) Differential distribution of the enzymes glutamate dehydrogenase and aspartate aminotransferase in cortical synaptic mitochondria contributes to metabolic compartmentation in cortical synaptic terminals. Neurochem. Int. 37, 229–241.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hassel, B. Carboxylation and anaplerosis in neurons and glia. Mol Neurobiol 22, 21–40 (2000). https://doi.org/10.1385/MN:22:1-3:021
Issue Date:
DOI: https://doi.org/10.1385/MN:22:1-3:021