Skip to main content
SpringerLink
Log in

Role of astrocytes in glutamate homeostasis: Implications for excitotoxicity

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Glutamate homeostasis in the brain is maintained by its well balanced release, uptake and metabolism. It appears that astrocytes play a prominent role in this context since they possess a very powerful battery of glutamate transporters. Thus, malfunction of astrocytic glutamate transporters will lead to an excessively high extracellular glutamate concentration which may result in neurodegeneration caused by the excitotoxic action of glutamate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Attwell D and SB Laughlin (2001) An energy budget for signalling in the grey matter of the brain.J. Cereb. Blood Flow Metab. 21, 1133–1145.

    Article  PubMed  CAS  Google Scholar 

  • Bak L, A Schousboe and HS Waagepetersen (2003) Characterizion of depolarization-coupled release of glutamate from cultured mouse cerebellar granule cells using DL-threo-ß-benzyloxyas-partate (DL-TBOA) do distinguish between the vesicular and cytoplasmic pools.Neurochem. Int. 43, 417–424.

    Article  PubMed  CAS  Google Scholar 

  • Benveniste H, J Drejer, A Schousboe and NH Diemer (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis.J. Neurochem. 43, 1369–1374.

    Article  PubMed  CAS  Google Scholar 

  • Bonde C, BW Kristensen, M Blaabjerg, TE Johansen, J Zimmer and M Meyer (2000) GDNF and neublastin protect against NMDA-induced excitotoxicity in hippocampal slice cultures.NeuroReport 11, 4069–4073.

    Article  PubMed  CAS  Google Scholar 

  • Bonde C, A Sarup, A Schousboe, G Gegelashvili, J Zimmer and J Noraberg (2003a) Neurotoxic and neuroprotective effects of the glutamate transporter inhibitor DL-threo-beta-benzylaspartate (DL-TBOA) during physiological and ischemia-like conditions.Neurochem. Int. 43, 371–380.

    Article  CAS  Google Scholar 

  • Bonde C, A Sarup, A Schousboe, G Gegelashvili, J Noraberg and J Zimmer (2003b) GDNF pre-treatment aggravates neuronal cell loss in oxygen-glucose deprived hippocampal slice cultures: a possible effect of glutamate transporter up-regulation.Neurochem. Int. 43, 381–388.

    Article  CAS  Google Scholar 

  • Choi DWand SM Rothman (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death.Annu. Rev. Neurosci. 13, 171–182.

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJL, JM McDonald, AS Gelbard, RF Gledhill and TE Duffy(1979) The metabolic fate of13N-labeled ammonia in rat brain.J. Biol. Chem. 154, 4982–4992.

    Google Scholar 

  • Danbolt NC (2001) Glutamate uptake.Prog. Neurobiol. 65, 1–105.

    Article  PubMed  CAS  Google Scholar 

  • Erecinska M and IA Silver (1990) Metabolism and role of glutamate in mammalian brain.Prog. Neurobiol. 35, 245–296.

    Article  PubMed  CAS  Google Scholar 

  • Ferrarese C, G Sala, R Riva, B Begni, C Zoia, L Tremolizzo, G Galimberti, A Millul, A Bastone, T Pennini, C Balzarini, L Frattola, E Beghi and Italian ALS Study group (2001) Decreased platelet glutamate uptake in patients with amyotrophic lateral sclerosis.Neurology 56, 270–272.

    PubMed  CAS  Google Scholar 

  • Fujita H, K Sato, TC Wen, Y Peng and M Sakanaka (1999) Differential expressions of glycine transporter 1 and three glutamate transporter mRNA in the hippocampus of gerbils with transient forebrain ischemia.J. Cereb. Blood Flow Metab. 19, 604–615.

    Article  PubMed  CAS  Google Scholar 

  • Gegelashvili G and A Schousboe (1998) Cellular distribution and kinetic properties of high-affinity glutamate transporters.Brain Res. Bull. 45, 233–238.

    Article  PubMed  CAS  Google Scholar 

  • Hagberg H, A Lehmann, M Sandberg, B Nyström, I Jacobsen, A Hamberger(1985) Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments.J. Cereb. Blood Flow Metab. 5, 413–419.

    PubMed  CAS  Google Scholar 

  • Hertz L, A Schousboe, N Boechler, S Mukerji and S Fedoroff (1978) Kinetic characteristics of the glutamate uptake into normal astrocytes in cultures.Neurochem. Res. 3, 1–14.

    Article  PubMed  CAS  Google Scholar 

  • Hertz L, R Dringen, A Schousboe and SR Robinson (1999) Astrocytes: Glutamate producers for neurons.J. Neurosci. Res. 57, 417–428.

    Article  PubMed  CAS  Google Scholar 

  • Jensen JB, DS Pickering and A Schousboe (2000) Depolarization-induced release of [3H]D-aspartate from GABAergic neurons caused by reversal of glutamate transporters.Int. J. Dev. Neurosci. 18, 309–315.

    Article  PubMed  CAS  Google Scholar 

  • Kvamme E, IA Torgner and B Roberg (2001) Kinetics and localization of brain phosphate activated glutaminase.J. Neurosci. Res. 66, 951–958.

    Article  PubMed  CAS  Google Scholar 

  • Levy LM (2002) Structure, function and regulation of glutamate transporters, In: Glutamate and GABA Receptors and Transporters. Structure, Function and Pharmacology (Egebjerg J, A Schousboe and P Krogsgaard-Larsen, Eds.) (Taylor and Francis: London), pp 307–336.

    Google Scholar 

  • McMahon HT and DG Nicholls (1991) Transmitter glutamate release from isolated nerve terminals: evidence for biphasic release and triggering by localized Ca2+.. J. Neurochem. 56, 86–94.

    Article  PubMed  CAS  Google Scholar 

  • Nicholls D and D Attwell (1990) The release and uptake of excitatory amino acids.Trends Pharmacol. Sci. 11, 462–468.

    Article  PubMed  Google Scholar 

  • Norenberg MD and A Martinez-Hernandez (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain.Brain Res. 161, 303–310.

    Article  PubMed  CAS  Google Scholar 

  • Palaiologos G, L Hertz and A Schousboe (1988) Evidence that aspartate amino transferase activity and ketodicarboxylate carrier function are essential for biosynthesis of transmitter glutamate.J. Neurochem. 51, 317–320.

    Article  PubMed  CAS  Google Scholar 

  • Phillis JW, J Ren and MH O’Regan (2000) Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-threo-beta-benzyloxyaspartate.Brain Res. 868, 105–112.

    Article  PubMed  CAS  Google Scholar 

  • Rao VLR, MK Baskaya, A Dogan, JD Rothstein and RJ Dempsey (1998) Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain.J. Neurochem. 70, 2020–2027.

    PubMed  CAS  Google Scholar 

  • Rao VLR, AM Rao, A Dogan, KK Bowen, J Hatcher, JD Rothstein and RJ Dempsey (2000) Glial glutamate transporter GLT-1 down-regulation precedes delayed neuronal death in gerbil hippocampus following transient global cerebral ischemia.Neurochem. Int. 36, 531–537.

    Article  PubMed  CAS  Google Scholar 

  • Rossi DJ, T Oshima and D Attwell (2000) Glutamate release in severe brain ischemia is mainly by reversed uptake.Nature 403, 316–321.

    Article  PubMed  CAS  Google Scholar 

  • Rothstein JD, LJ Martin and RW Kuncl (1992) Decreased brain and spinal cord glutamate transport in amyotrophic lateral sclerosis.New Engl. J. Med. 316, 1464–1468.

    Article  Google Scholar 

  • Rothstein JD, M Van Kammen, AI Levely, L Martin and RW Kuncl (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.Ann. Neurol. 38, 73–84.

    Article  PubMed  CAS  Google Scholar 

  • Rothstein JD, M Dykes-Hoberg, CA Pardo, LA Bristol, L Jin, RW Kuncl, Y Kanai, MA Hediger, Y Wang, JP Schielke and DF Welty (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate.Neuron 16, 675–686.

    Article  PubMed  CAS  Google Scholar 

  • Sala G, S Beretta, C Ceresa, L Mattavelli, C Zoia, L Tremolizzo, A Ferri, MT Carri and C Ferrarese (2004) Impairment of glutamate transport and increased vulnerability to oxidative stress in neuroblastoma SH-SY5Y cells expressing a Cu, Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis.Neurochem. Int. 46, 227–234.

    Article  PubMed  CAS  Google Scholar 

  • Sandberg M, SP Butcher and H Hagberg (1986) Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia:in vivo dialysis of rat hippocampus.J. Neurochem. 47, 178–184.

    PubMed  CAS  Google Scholar 

  • Schousboe A and A Frandsen (1995) Glutamate receptors and neurotoxicity, In:CNS Neurotransmitters and Neuromodulators:Glutamate (Stone TW, Ed.) (CRC Press: Boca Raton, FL), pp 239–251.

    Google Scholar 

  • Schousboe A and HS Waagepetersen (2004) Role of astrocytes in homeostasis of glutamate and GABA during physiological and pathophysiological conditions, In:Non-Neuronal Cells of the Nervous System:Function and Dysfunction (Hertz L, Ed.) (Elsevier: Amsterdam, NL), pp 461–474.

    Google Scholar 

  • Schousboe A, G Svenneby and L Hertz (1977) Uptake and metabolism of glutamate in astrocytes cultured from dissociated mouse brain hemispheres.J. Neurochem. 29, 999–1005.

    Article  PubMed  CAS  Google Scholar 

  • Shank RP, GS Bennett, SO Freytag and GL Campbell (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools.Brain Res. 329, 364–367.

    Article  PubMed  CAS  Google Scholar 

  • Szatkowski M, B Barbour and D Attwell (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake.Nature 348, 443–446.

    Article  PubMed  CAS  Google Scholar 

  • Torp R, D Lekieffre, LM Levy, FM Haug, NC Danbolt, BS Meldrum and OP Ottersen (1995) Reduced postischemic expression of a glial glutamate transporter, GLT1, in the rat hippocampus.Exp. Brain Res. 103, 51–58.

    Article  PubMed  CAS  Google Scholar 

  • Volterra A and J Meldolesi (2004) Quantal release of transmitter: not only from neurons but from astrocytes as well?, In:Neuroglia 2nd Edition (Kettenmann H and BR Ransom, Eds.) (Oxford Univ Press: UK), pp 190–201.

    Google Scholar 

  • Waagepetersen HS, U Sonnewald, OM Larsson and A Schousboe (2001) Multiple compartments with different metabolic characteristics are involved in biosynthesis of intracellular and released glutamine and citrate in astrocytes.Glia 35, 246–252.

    Article  PubMed  CAS  Google Scholar 

  • Waagepetersen HS, H Qu, L Hertz, U Sonnewald and A Schousboe (2002) Demonstration of pyruvate recycling in primary cultures of neocortical astrocytes but not in neurons.Neurochem. Res. 27, 1431–1437.

    Article  PubMed  CAS  Google Scholar 

  • Wadiche JI, JL Arriza, SG Amara and MP Kavanaugh (1995) Kinetics of a human glutamate transporter.Neuron 14, 1019–1027.

    Article  PubMed  CAS  Google Scholar 

  • Yu ACH, J Drejer, L Hertz and A Schousboe (1983) Pyruvate car-boxylase activity in primary cultures of astrocytes and neurons.J. Neurochem. 41, 1484–1487.

    Article  PubMed  CAS  Google Scholar 

  • Zaganas I, HS Waagepetersen, P Georgopoupolos, U Sonnewald, A Plaitakis and A Schousboe (2001) Differential expression of glutamate dehydrogenase in cultured neurons and astrocytes from mouse cerebellum and cerebral cortex.J. Neurosci. Res. 66, 909–913.

    Article  PubMed  CAS  Google Scholar 

  • Zieminska E, W Hilgier, HS Waagepetersen, L Hertz, U Sonnewald, A Schousboe and J Albrecht (2004) Analysis of glutamine accumulation in rat brain mitochondria in the presence of a glutamine uptake inhibitor, histidine, reveals glutamine pools with a distinct access to deamidation.Neurochem. Res. 29, 2121–2123.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100, Copenhagen, DK, Denmark

    Arne Schousboe & Helle S. Waagepetersen

Authors
  1. Arne Schousboe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helle S. Waagepetersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arne Schousboe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schousboe, A., Waagepetersen, H.S. Role of astrocytes in glutamate homeostasis: Implications for excitotoxicity. neurotox res 8, 221–225 (2005). https://doi.org/10.1007/BF03033975

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033975

Keywords

Search

Navigation