Abstract
Glutamate metabolism in the brain is extremely complex not only involving a large variety of enzymes but also a tight partnership between neurons and astrocytes, the latter cells being in control of de novo synthesis of glutamate. This review provides an account of the processes involved, i.e. pyruvate carboxylation and recycling as well as the glutamate–glutamine cycle, focusing on the many seminal contributions from Dr. Mary McKenna. The ramification of the astrocytic end feet allowing contact and control of hundreds of thousands of synapses at the same time obviously puts these cells in a prominent position to regulate neural activity. Additionally, the astrocytes take active part in the neurotransmission processes by releasing a variety of gliotransmitters including glutamate. Hence, the term “the tripartite synapse”, in which there is an active and dynamic interplay between the pre- and post-synaptic neurons and the ensheathing astrocytes, has been coined. The studies of Mary McKenna and her colleagues over several decades have been of paramount importance for the elucidation of compartmentation in astrocytes and synaptic terminals and the intricate metabolic processes underlying the glutamatergic neurotransmission process.
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References
Erecinska M, Silver IA (1990) Metabolism and role of glutamate in mammalian brain. Prog Neurobiol 35:245–296
Waagepetersen HS, Sonnewald U, Schousboe A (2007) Glutamine, glutamate, and GABA: metabolic aspects. In: Oja S, Schousboe A, Kontro P (eds) Handbook of neurochemistry and molecular neurobiology, 3rd edition: amino acids and peptides in the nervous system. Springer, NY, pp 1–21
Hertz L (1979) Functional interactions between neurons and astrocytes. I. Turnover and metabolism of putative amino acid neurotransmitters. Prog Neurobiol 13:277–323
Schousboe A (1981) Transport and metabolism of glutamate and GABA in neurons and glial cells. Int Rev Neurobiol 22:1–45
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
Schousboe A (2013) Glutamate neurotoxicity related to energy failure. In: Kostrzewa RM (ed) Handbook of neurotoxicity. Springer Science Media, NY, pp 1299–1310
Curtis DR, Phillis JW, Watkins JC (1959) Chemical excitation of spinal neurons. Nature 183:611–612
Fonnum F (1984) Glutamate: a neurotransmitter in mammalian brain. J Neurochem 42:1–11
Verkhratsky A, Schousboe A, Parpura V (2014) Glutamate and ATP: the crossroads of signaling and metabolism in the brain. Adv Neurobiol 11:1–12
McKenna MC, Dienel GA, Sonnewald U, Waagepetersen HS, Schousboe A (2012) Energy metabolism in the brain. In: Siegel GJ, Albers RW, Brady ST, Price DI (eds) Basic neurochemistry: molecular, cellular and medical aspects, 8th edn. Elsevier-Academic Press, London, pp 200–231
McKenna MC (2013) Glutamate pays its own way in astrocytes. Front Endocrinol 4:1–6. Article 191. doi:10.3389/fendo.2013.00191
Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC (2014) Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol 11:13–30
Norenberg MD, Martinez-Hernandez A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310
Schousboe A, Hertz L, Svenneby G, Kvamme E (1979) Phosphate activated glutaminase activity and glutamine uptake in primary cultures of astrocytes. J Neurochem 32:943–950
Kvamme E, Torgner IA, Roberg B (2001) Kinetics and localization of brain phosphate activated glutaminase. J Neurosci Res 66:951–958
Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH-C, Han X, Akano T, Wang S, Goldman SA, Nedergaard M (2007) The transcriptome and metabolic gene signature of protoplasmic astrocytes in adult murine cortex. J Neurosci 27:12255–12266
Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM (2001) Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 76:1712–1723
Schousboe A, Walls AB, Bak LK, Waagepetersen HS (2015) Astroglia and brain metabolism: focus on energy and neurotransmitter amino acid homeostasis. In: Verkhratsky A, Parpura V (eds) Colloquium series on neuroglia in biology and medicine from physiology to disease. Morgan & Claypool Life Sciences, San Rafael, CA, pp 1–63
Schousboe A, Svenneby G, Hertz L (1977) Uptake and metabolism of glutamate in astrocytes cultured from dissociated mouse brain hemispheres. J Neurochem 29:999–1005
Larsson OM, Drejer J, Kvamme E, Svenneby G, Hertz L, Schousboe A (1985) Ontogenetic development of GABA and glutamate metabolizing enzymes in cultured cerebral cortex interneurons and in cerebral cortex in vivo. Int J Dev Neurosci 3:177–185
Kvamme E, Svenneby G, Torgner IA, Drejer J, Schousboe A (1985) Postnatal development of glutamate metabolizing enzymes in hippocampus from mice. Int J Dev Neurosci 3:359–364
McKenna MC, Stevenson JH, Huang X, Hopkins I (2000) Differential distribution of the enzymes glutamate dehydrogenase and aspartase aminotransferase in cortical mitochondria contributes to metabolic compartmentation in cortical synaptic terminals. Neurochem Int 37:229–241
McKenna MC (2011) Glutamate dehydrogenase in brain mitochondria: do lipid modifications and transient metabolon formation influence enzyme activity? Neurochem Int 59:525–533
Waagepetersen HS, Bakken IJ, Larsson OM, Sonnewald U, Schousboe A (1998) Comparison of lactate and glucose metabolism in cultured neocortical neurons using 13C NMR spectroscopy. Dev Neurosci 20:310–321
McKenna MC, Tildon JT, Stevenson JH, Boatright R, Huang S (1993) Regulation of energy metabolism in synaptic terminals and cultured rat brain astrocytes: differences revealed using aminooxyacetate. Dev Neurosci 15:320–329
Sonnewald U, McKenna MC (2002) Metabolic compartmentation in cortical synaptosomes: influence of glucose and preferential incorporation of endogenous glutamate into GABA. Neurochem Res 27:43–50
Schousboe A, Westergaard N, Sonnewald U, Petersen SB, Huang R, Peng L, Hertz L (1993) Glutamate and glutamine metabolism and compartmentation in astrocytes. Dev Neurosci 15:359–366
McKenna MC, Tildon JT, Stevenson JH, Huang X (1996) New insights into the compartmentation of glutamate and glutamine in cultured rat brain astrocytes. Dev Neurosci 18:380–390
McKenna MC (2007) The glutamate–glutamine cycle is not stoichiometric: fates of glutamate in the brain. J Neurosci Res 85:3347–3358
Balazs R (1965) Control of glutamate oxidation in brain and liver mitochondrial systems. Biochem J 95:497–508
Farinelli SE, Nicklas WJ (1992) Glutamate metabolism in rat cortical astrocyte cultures. J Neurochem 58:1905–1915
Yu AC, Schousboe A, Hertz L (1982) Metabolic fate of 14C-labelled glutamate in astrocytes in primary cultures. J Neurochem 39:540–545
Hertz L (2013) The glutamate–glutamine (GABA) cycle: importance of late postnatal development and potential reciprocal interactions between biosynthesis and degradation. Front Endocrinol 4: article 59. doi:10.3389/fendo.2013.0059
McKenna MC, Sonnewald U, Huang X, Stevenson J, Zielke HR (1996) Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J Neurochem 66:386–393
Pajecka K, Nissen JD, Stridh MH, Skytt DM, Schousboe A, Waagepetersen HS (2015) Glucose replaces glutamate as energy substrate to fuel glutamate uptake in glutamate dehydrogenase-deficient astrocytes. J Neurosci Res. doi:10.1002/jnr.23568
Nissen JD, Pajecka K, Stridh MH, Skytt DM, Waagepetersen HS (2015) Dysfunctional TCA-cycle metabolism in glutamate dehydrogenase deficient astrocytes. Glia. doi:10.1002/glia.22895
Cerdan S, Kunnecke B, Seelig J (1990) Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. J Biol Chem 265:12916–12926
Sonnewald U, Westergaard N, Jones P, Taylor A, Bachelard HS, Schousboe A (1996) Metabolism of [U-13C5]glutamine in cultured astrocytes studied by NMR spectroscopy: first evidence of astrocytic pyruvate recycling. J Neurochem 67:2566–2572
Waagepetersen H, Qu H, Hertz L, Sonnewald U, Schousboe A (2002) Demonstration of pyruvate recycling in primary cultures of neocortical astrocytes but not in neurons. Neurochem Res 27:1431–1437
Olstad E, Olsen GM, Qu H, Sonnewald U (2007) Pyruvate recycling in cultured neurons from cerebellum. J Neurosci Res 85:3318–3325
Amaral AI, Teixeira AP, Sonnewald U, Alves PM (2011) Estimation of intracellular fluxes in cerebellar neurons after hypoglycemia: importance of the pyruvate recycling pathway and glutamine oxidation. J Neurosci Res 89:700–710
Scafidi S, O’Brian J, Hopkins I, Robertson C, Fiskum G, McKenna MC (2011) Delayed cerebral oxidative glucose metabolism afte traumatic brain injury in young rats. J Neurochem 109(Suppl. 1):189–197
Sonnewald U (2014) Glutamate synthesis has to be matched by its degradation—where do all the carbons go? J Neurochem 131:399–406
Sonnewald U, Westergaard N, Petersen SB, Unsgaard G, Schousboe A (1993) Metabolism of [U-13C]glutamate in astrocytes studied by 13C NMR spectroscopy: incorporation of more label into lactate than into glutamine demonstrates the importance of the tricarboxylic acid cycle. J Neurochem 61:1179–1182
Schousboe A (2012) Studies of brain metabolism: a historical perspective. Adv Neurobiol 4:909–920
Patel MS (1974) The relative significance of CO2-fixing enzymes in the metabolism of the brain. J Neurochem 22:717724
Yu AC, Drejer J, Hertz L, Schousboe A (1983) Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J Neurochem 42:1484–1487
Shank RP, Bennett GS, Freytag SO, Campbell GL (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools. Brain Res 329:364–367
Cesar M, Hamprecht B (1995) Immunocytochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase. J Neurochem 64:2312–2318
Cotman CW, Foster A, Lanthorn T (1981) An overview of glutamate as a neurotransmitter. Adv Biochem Psychopharmacol 27:1–27
Westergaard N, Sonnewald U, Schousboe A (1995) Metabolic trafficking between neurons and astrocytes: the glutamate–glutamine cycle revisited. Dev Neurosci 17:203–211
Sonnewald U, Westergaard N, Schousboe A (1997) Glutamate transport and metabolism in astrocytes. Glia 21:56–63
Chaudhry FA, Reimer AJ, Edwards RH (2002) The glutamine commute: take the N line and transfer to the A. J Cell Biol 157:349–355
Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98:641–653
Leke R, Escobar TDC, Rama Rao KV, Reverbel da Silveira T, Norenberg MD, Schousboe A (2015) Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy. Neurochem Int 88:32–37. doi:10.1016/j.neuint.2015.03.005
Palaiologos G, Hertz L, Schousboe A (1988) Evidence that aspartate aminotransferase activity and ketodicarboxylate carrier function are essential for biosynthesis of transmitter glutamate. J Neurochem 51:317–320
Kihara M, Kubo T (1989) Aspartate aminotransferease for synthesis of transmitter glutamate in the medulla oblongata: effect of aminooxyacetic acid and 2-oxoglutarate. J Neurochem 52:1127–1134
Shank RP, Baldy WJ, Ash CH (1989) Glutamine and 2-oxoglutarate as metabolic precursors of the transmitter pools of glutamate and GABA: correlation of regional uptake by rat brain synaptosomes. Neurochem Res 14:371–376
Peng L, Schousboe A, Hertz L (1991) Utilization of alpha-ketoglutarate as a precursor for glutamate in cultured cerebellar granule cells. Neurochem Res 16:29–34
Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553
Oberheim NA, Takano T, Han X, He W, Lin JH, Xu Q, Wyatt JD, Pilcher W, Ojemann JG, Ransom BR, Goldman SA, Nedergaard M (2009) Uniquely hominid features of adult human astrocytes. J Neurosci 29:3276–3287
Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia the unacknowledged partner. Trends Neurosci 22:208–215
Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27
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Schousboe, A. A Tribute to Mary C. McKenna: Glutamate as Energy Substrate and Neurotransmitter—Functional Interaction Between Neurons and Astrocytes. Neurochem Res 42, 4–9 (2017). https://doi.org/10.1007/s11064-015-1813-9
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DOI: https://doi.org/10.1007/s11064-015-1813-9