The classical concept regarding compartmentation of brain metabolism pertinent to the two neurotrans-mitter amino acids, glutamate and GABA (γ-aminobutyrate), operates with different pools of glutamate and glutamine in different cell types, that is, pools that have different sizes and turnover rates. As a result of more sophisticated technology (e.g., nuclear magnetic resonance spectroscopy and mass spectrometry used in relation to cultured neurons and astrocytes), a more complex scenario is emerging. Hence, both neurons and astrocytes exhibit a compartmentalized metabolism that very likely relates to individual cells containing mitochondrial populations having different metabolic roles. Models for this in neurons and astro-cytes, respectively, are presented. The functional implications of this for the homeostatic mechanisms regulating the levels of neurotransmitter glutamate and GABA are discussed in relation to development of therapeutic strategies for neurological disorders in which these transmitters are believed to play important roles.
Get full access to this article
View all access options for this article.
References
1.
Balázs R, Patel AJ, Richter D. 1973. Metabolic compartments in the brain: their properties and relation to morphological structures. In: Balázs R, Cremer JE, editors. Metabolic compartmentation in the brain. London: McMillan . p 167-184.
2.
Belhage B, Hansen GH, Schousboe A. 1993. Depolarization by K+ and glutamate activates different neurotransmitter release mechanisms in GABAergic neurons: vesicular versus non-vesicular release of GABA . J Neurosci54: 1019-1034 .
3.
Berl S. 1965. Compartmentation of glutamic acid metabolism in developing cerebral cortex . J Biol Chem240: 2047-2054 .
4.
Berl S, Clarke DD. 1969. Compartmentation of amino acid metabolism. In: Lajtha A, editor. Handbook of neurochemistry. Vol. 2, first ed. Edit. New York: Plenum . p 447-472.
5.
Berl S, Lajtha A, Waelsch H. 1961. Amino acid and protein metabolism of the brain—VI. Cerebral compartments of glutamic acid metabolism . J Neurochem7: 322-332 .
6.
Bouzier AK, Goodwin R, de Gannes FM, Valeins H, Voisin P, Canioni P, and others. 1998. Compartmentation of lactate and glucose metabolism in C6 glioma cells. A 13C and 1H NMR study . J Biol Chem273: 27162-27169 .
7.
Cruz F, Villalba M, Garcia-Espinosa MA, Ballesteros P, Bogonez E, Satrustegui J, and others. 2001. Intracellular compartmentation of pyruvate in primary cultures of cortical neurons as detected by (13)C NMR spectroscopy with multiple (13)C labels . J Neurosci Res66: 771-781 .
8.
Drejer J, Honoré T, Schousboe A. 1987. Excitatory amino acid induced release of 3H-GABA from cultured mouse cerebral cortex interneurons . J Neurosci7: 2910-2916 .
9.
Laake JH, Takumi Y, Eidet J, Torgner IA, Roberg B, Kvamme E, and others. 1999. Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum . Neuroscience4: 1137-1151 .
10.
Lai JC, Walsh JM, Dennis SC, Clark JB. 1977. Synaptic and non-synaptic mitochondria from rat brain: isolation and characterization . J Neurochem28: 625-631 .
11.
Lajtha A, Berl S, Waelsch H. 1959. Amino acid and protein metabolism of the brain—IV. The metabolism of glutamic acid . J Neurochem3: 322-332 .
12.
Larsson OM, Drejer J, Kvamme E, Svenneby G, Hertz L, Schousboe A. 1985. Ontogenetic development of glutamate and GABA metabolizing enzymes in cultured cerebral cortex interneurons and in cerebral cortex in vivo . Int J Devl Neurosci3: 177-185 .
13.
Löscher. 1998. New visions in the pharmacology of anticonvulsion . Eur J Pharmacol342: 1-13 .
14.
Margineantu DH, Brown RM, Brown GK, Marcus AH, Capaldi RA. 2002. Heterogenous distribution of pyruvate dehydrogenase in the matrix of mitochondria . Mitochondrion1: 327-338 .
15.
Martinez-Hernandez A, Bell KP, Norenberg MD. 1977. Glutamine synthetase: glial localization in brain . Science195: 1356-1358 .
16.
Mason GF, Gruetter R, Rothman DL, Behar KL, Shulman RG, Novotny EJ. 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 Met15: 12-25 .
17.
McKenna MC, Tildon JT, Stevenson JH, Hopkins IB. 1994. Energy metabolism in cortical synaptic terminals from weanling and mature rat brain: evidence for multiple compartments of tricar-boxylic acid cycle activity . Dev Neurosci16: 291-300 .
18.
McKenna MC, Tildon JT, Stevenson JH, Huang X. 1996. New insight into the compartmentation of glutamate and glutamine in cultured rat brain astrocytes . Dev Neurosci18: 380-391 .
19.
Qu H, Faero E, Jorgensen P, Dale O, Gisvold SE, Unsgard G, and others. 1999. Decreased glutamate metabolism in cultured astrocytes in the presence of thiopental . Biochem Pharmacol58: 1075-1080 .
20.
Roberts E, Rothstein M, Baxter CF. 1958. Some metabolic studies of g-aminobutyric acid . Proc Soc Exptl Biol97: 796-802 .
21.
Schousboe A, Sonnewald U, Waagepetersen HS. 2003. Differential roles of alanine in GABAergic and glutamatergic neurons . Neurochem Int. 43: 311-315 .
22.
Schousboe A, Westergaard N, Sonnewald U, Petersen SB, Huang R, Peng L, and others. 1993. Glutamate and glutamine metabolism and compartmentation in astrocytes . Dev Neurosci15: 359-366 .
23.
Schousboe A, Westergaard N, Waagepetersen HS, Larsson OM, Bakken IJ, Sonnewald U. 1997. Trafficking between glia and neurons of TCA cycle intermediates and related metabolites . Glia21: 99-105 .
24.
Sonnewald U, Westergaard N, Hassel B, Muller TB, Unsgard G, Fonnum F, and others. 1993. NMR spectroscopic studies of 13C acetate and 13C glucose metabolism in neocortical astrocytes: evidence for mitochondrial heterogeneity . Dev Neurosci15: 351-358 .
25.
Waagepetersen HS, Bakken IJ, Larsson OM, Sonnewald U, Schousboe A. 1998a. Comparison of lactate and glucose metabolism in cultured neocortical neurons and astrocytes using 13C NMR spectroscopy . Dev Neurosci20: 310-320 .
26.
Waagepetersen HS, Bakken IJ, Larsson OM, Sonnewald U, Schousboe A. 1998b. Metabolism of lactate in cultured GABAergic neurons studied by 13C-NMR spectroscopy . J Cereb Blood Flow Met18: 109-117 .
27.
Waagepetersen HS, Sonnewald U, Gegelashvili G, Larsson OM, Schousboe A. 2001. Metabolic distinction between vesicular and cytosolic GABA in cultured GABAergic neurons using 13C MRS . J Neurosci Res63: 347-355 .
28.
Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. 1999. Synthesis of vesicular GABA from glutamine involves TCA cycle metabolism i neocortical neurons . J Neurosci Res57: 342-349 .
29.
Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. 2000a. Compartmentation of TCA cycle metabolism in cultured neocortical neurons revealed by 13C MR spectroscopy . Neurochem Int36: 349-358 .
30.
Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. 2000b. A possible role of alanine for ammonia transfer between astrocytes and glutamatergic neurons . J Neurochem75: 471-479 .
31.
Waagepetersen HS, Sonnewald U, Larsson OM, Schousboe A. 2001. Multiple compartments with different metabolic characteristics are involved in biosynthesis of intracellular and released glutamine and citrate in astrocytes . Glia35: 246-252 .
32.
Westergaard N, Sonnewald U, Petersen SB, Schousboe A. 1995. Glutamate and glutamine metabolism in cultured GABAergic neurons studied by 13C NMR spectroscopy may indicate compartmentation and mitochondrial heterogeneity . Neurosci Lett185: 24-28 .
33.
Westergaard N, Sonnewald U, Schousboe A. 1995. Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited . Dev Neurosci17: 203-211 .
34.
Westergaard N, Sonnewald U, Unsgård G, Peng L, Hertz L, Schousboe A. 1994. Uptake, release and metabolism of citrate in neurons and astrocytes in primary cultures . J Neurochem62: 1727-1733 .
35.
Van den Berg CJ, Garfinkel D. 1971. A simulation study of brain compartments: metabolism of glutamate and related substances in mouse brain . Biochem J23: 211-218 .
36.
Van den Berg CJ, Matheson DF, Ronda G, Reijnierse GLA, Blokhuis GGD, Kroon MC, and others. 1975. A model of glutamate metabolism in brain: a biochemical analysis of a heterogenous structure. In: Berl S, Clarke DD, Schneider D, editors. Metabolic compartmentation and neurotransmission: relation to brain structure and function. New York: Plenum . p 515-543.
37.
Zwingmann C, Richter-Landsberg C, Leibfritz D. 2001. 13C isotopomer analysis of glucose and alanine metabolism reveals cytosolic pyruvate compartmentation as part of energy metabolism in astrocytes . Glia34: 200-212 .
