Specialized Neurotransmitter Transporters in Astrocytes

  • Yongjie Yang
  • Jeffrey D. Rothstein

In the central nervous system (CNS), synaptic neurotransmission is a fundamental and critical process for neurons to receive and process information. In this process, neurotransmitters, the chemical signals, are released from presynaptic neuronal terminals upon stimulus to activate receptors on postsynaptic membranes. The inactivation of most released neurotransmitters occurs via efficient reuptake of neurotransmitters into the presynaptic nerve terminal and/or adjacent glial cells. Astrocytes, the most abundant cell in the CNS, express various transporter proteins on the plasma membrane for the uptake of neurotransmitters, forming an indispensable unit of functional synaptic neurotransmission. Transporters are vital for the normal CNS physiology by maintaining neurotransmitter homeostasis, modulating synaptic transmission and preventing neurological damage induced by the imbalance of neurotransmitters. The distribution and functional importance of neurotransmitter transporters in...


Amyotrophic Lateral Sclerosis Amyotrophic Lateral Sclerosis Patient Glutamate Transporter Bergmann Glia GLT1 Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Amyotrophic lateral sclerosis


IJ-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid


Amyloid β a4 precursor protein


Bone morphogenetic protein


Cyclic adenosine monophosphate


Central nervous system


Cerebrospinal fluid


Excitatory amino acid carrier


Excitatory amino acid transporter


Epidermal growth factor


Electron microscopy


Excitatory postsynaptic current


γ-aminobutyric acid


Glutamic acid decarboxylase


GABA transporter


l-glutamate/l-aspartate transporter


l-glutamate transporter


glycine transporter


Huntington”s disease




Leukemia-inhibitory factor


Inhibitory postsynaptic current


Metabotropic glutamate receptor


Neuronal conditioned medium


Nuclear transcription factor κB




Parkinson”s disease


Phosphatidylinositol 3-kinase


Protein kinase C


Solute carrier


Superoxide dismutase


Transforming growth factor α


4,5,6,7-tetrahydroisoxazolo [4,5-c]pyridin-3-ol


Transmembrane helix


Transmembrane domains


Tumor necrosis factor-α


Untranslated region


  1. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32:1–14.PubMedCrossRefGoogle Scholar
  2. Aragon C, Lopez-Corcuera B (2003) Structure, function and regulation of glycine neurotransporters. Eur J Pharmacol 479:249–262.PubMedCrossRefGoogle Scholar
  3. Arriza JL, Eliasof S, Kavanaugh MP, Amara SG (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94:4155–4160.PubMedCrossRefGoogle Scholar
  4. Arundine M, Tymianski M (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34:325–337.PubMedCrossRefGoogle Scholar
  5. Arzberger T, Krampfl K, Leimgruber S, Weindl A (1997) Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington’s disease – an in situ hybridization study. J Neuropathol Exp Neurol 56:440–454.PubMedCrossRefGoogle Scholar
  6. Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, Kuzume H, Sanbo M, Yagi T, Obata K (1997) Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 94:6496–6499.PubMedCrossRefGoogle Scholar
  7. Baude A, Nusser Z, Roberts JD, Mulvihill E, McIlhinney RA, Somogyi P (1993) The metabotropic glutamate receptor (mGluR1α) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11:771–787.PubMedCrossRefGoogle Scholar
  8. Beart PM, O’Shea RD (2007) Transporters for l. -glutamate: an update on their molecular pharmacology and pathological involvement Br J Pharmacol 150:5–17.PubMedCrossRefGoogle Scholar
  9. Berger AJ, Dieudonne S, Ascher P (1998) Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol 80:3336–3340.PubMedGoogle Scholar
  10. Berger UV, Hediger MA (1998) Comparative analysis of glutamate transporter expression in rat brain using differential double in situ hybridization. Anat Embryol 198:13–30.PubMedCrossRefGoogle Scholar
  11. Berger UV, Hediger MA (2000) Distribution of the glutamate transporters GLAST and GLT-1 in rat circumventricular organs, meninges, and dorsal root ganglia. J Comp Neurol 421:385–399.PubMedCrossRefGoogle Scholar
  12. Berger UV, DeSilva TM, Chen W, Rosenberg PA (2005) Cellular and subcellular mRNA localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ hybridization. J Comp Neurol 492:78–89.PubMedCrossRefGoogle Scholar
  13. Bergles DE, Jahr CE (1997) Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19:1297–1308.PubMedCrossRefGoogle Scholar
  14. Bergles DE, Jahr CE (1998) Glial contribution to glutamate uptake at Schaffer collateral–commissural synapses in the hippocampus. J Neurosci 18:7709–7716.PubMedGoogle Scholar
  15. Bernabe A, Mendez JA, Hernandez-Kelly LC, Ortega A (2003) Regulation of the Na+-dependent glutamate/aspartate transporter in rodent cerebellar astrocytes. Neurochem Res 28:1843–1849.PubMedCrossRefGoogle Scholar
  16. Betz H, Gomeza J, Armsen W, Scholze P, Eulenburg V (2006) Glycine transporters: essential regulators of synaptic transmission. Biochem Soc Trans 34:55–58.PubMedCrossRefGoogle Scholar
  17. Borden LA, Smith KE, Hartig PR, Branchek TA, Weinshank RL (1992) Molecular heterogeneity of the γ-aminobutyric acid (GABA) transport system. Cloning of two novel high affinity GABA transporters from rat brain. J Biol Chem 267:21098–21104.Google Scholar
  18. Brasnjo G, Otis TS (2001) Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression. Neuron 31:607–616.PubMedCrossRefGoogle Scholar
  19. Bristol LA, Rothstein JD (1996) Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Ann Neurol 39:676–679.PubMedCrossRefGoogle Scholar
  20. Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338.PubMedCrossRefGoogle Scholar
  21. Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19:3248–3257.PubMedGoogle Scholar
  22. Chaudhry FA, Lehre KP, van Lookeren Campagne M, Ottersen OP, Danbolt NC, Storm-Mathisen J (1995) Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15:711–720.PubMedCrossRefGoogle Scholar
  23. Chen NH, Reith ME, Quick MW (2004a) Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch 447:519–531.CrossRefGoogle Scholar
  24. Chen S, Diamond JS (2002) Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina. J Neurosci 22:2165–2173.PubMedGoogle Scholar
  25. Chen W, Aoki C, Mahadomrongkul V, Gruber CE, Wang GJ, Blitzblau R, Irwin N, Rosenberg PA (2002) Expression of a variant form of the glutamate transporter GLT1 in neuronal cultures and in neurons and astrocytes in the rat brain. J Neurosci 22:2142–2152.PubMedGoogle Scholar
  26. Chen W, Mahadomrongkul V, Berger UV, Bassan M, DeSilva T, Tanaka K, Irwin N, Aoki C, Rosenberg PA (2004b) The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J Neurosci 24:1136–1148.CrossRefGoogle Scholar
  27. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634.PubMedCrossRefGoogle Scholar
  28. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23:1261–1276.PubMedCrossRefGoogle Scholar
  29. Clark BA, Cull-Candy SG (2002) Activity-dependent recruitment of extrasynaptic NMDA receptor activation at an AMPA receptor-only synapse. J Neurosci 22:4428–4436.PubMedGoogle Scholar
  30. Cubelos B, Gimenez C, Zafra F (2005) Localization of the GLYT1 glycine transporter at glutamatergic synapses in the rat brain. Cereb Cortex 15:448–459.PubMedCrossRefGoogle Scholar
  31. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105.PubMedCrossRefGoogle Scholar
  32. Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548.PubMedCrossRefGoogle Scholar
  33. Deneen B, Ho R, Lukaszewicz A, Hochstim CJ, Gronostajski RM, Anderson DJ (2006) The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52:953–968.PubMedCrossRefGoogle Scholar
  34. Diamond JS, Jahr CE (1997) Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci 17:4672–4687.PubMedGoogle Scholar
  35. Domercq M, Sanchez-Gomez MV, Areso P, Matute C (1999) Expression of glutamate transporters in rat optic nerve oligodendrocytes. Eur J Neurosci 11:2226–2236.PubMedCrossRefGoogle Scholar
  36. Drejer J, Meier E, Schousboe A (1983) Novel neuron-related regulatory mechanisms for astrocytic glutamate and GABA high affinity uptake. Neurosci Lett 37:301–306.PubMedCrossRefGoogle Scholar
  37. During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610.PubMedCrossRefGoogle Scholar
  38. During MJ, Ryder KM, Spencer DD (1995) Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 376:174–177.PubMedCrossRefGoogle Scholar
  39. Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T, Kengaku M (2005) DNER acts as a neuron-specific Notch ligand during Bergmann glial development. Nat Neurosci 8:873–880.PubMedGoogle Scholar
  40. Eliasof S, Arriza JL, Leighton BH, Amara SG, Kavanaugh MP (1998a) Localization and function of five glutamate transporters cloned from the salamander retina. Vision Res 38:1443–1454.CrossRefGoogle Scholar
  41. Eliasof S, Arriza JL, Leighton BH, Kavanaugh MP, Amara SG (1998b) Excitatory amino acid transporters of the salamander retina: identification, localization, and function. J Neurosci 18:698–712.Google Scholar
  42. Eng DL, Lee YL, Lal PG (1997) Expression of glutamate uptake transporters after dibutyryl cyclic AMP differentiation and traumatic injury in cultured astrocytes. Brain Res 778:215–221.PubMedCrossRefGoogle Scholar
  43. Erlander MG, Tobin AJ (1991) The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem research 16:215–226.CrossRefGoogle Scholar
  44. Eulenburg V, Armsen W, Betz H, Gomeza J (2005) Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci 30:325–333.PubMedCrossRefGoogle Scholar
  45. Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375:599–603.PubMedCrossRefGoogle Scholar
  46. Figiel M, Maucher T, Rozyczka J, Bayatti N, Engele J (2003) Regulation of glial glutamate transporter expression by growth factors. Exp Neurol 183:124–135.PubMedCrossRefGoogle Scholar
  47. Figiel M, Allritz C, Lehmann C, Engele J (2007) Gap junctional control of glial glutamate transporter expression. Mol Cell Neurosci 35:130–137.PubMedCrossRefGoogle Scholar
  48. Flowers JM, Powell JF, Leigh PN, Andersen P, Shaw CE (2001) Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. Ann Neurol 49:643–649.PubMedCrossRefGoogle Scholar
  49. Furness DN, Lehre KP (1997) Immunocytochemical localization of a high-affinity glutamate–aspartate transporter, GLAST, in the rat and guinea-pig cochlea. The Eur J Neurosci 9:1961–1969.CrossRefGoogle Scholar
  50. Furuta A, Rothstein JD, Martin LJ (1997) Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J Neurosci 17:8363–8375.PubMedGoogle Scholar
  51. Gegelashvili G, Civenni G, Racagni G, Danbolt NC, Schousboe I, Schousboe A (1996) Glutamate receptor agonists up-regulate glutamate transporter GLAST in astrocytes. Neuroreport 8:261–265.PubMedCrossRefGoogle Scholar
  52. Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 37:163–170.PubMedCrossRefGoogle Scholar
  53. Gegelashvili G, Robinson MB, Trotti D, Rauen T (2001) Regulation of glutamate transporters in health and disease. Prog Brain Res 132:267–286.PubMedCrossRefGoogle Scholar
  54. Genoud C, Quairiaux C, Steiner P, Hirling H, Welker E, Knott GW (2006) Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLoS Biol 4:e343.PubMedCrossRefGoogle Scholar
  55. Ginsberg SD, Martin LJ, Rothstein JD (1995) Regional deafferentation down-regulates subtypes of glutamate transporter proteins. J Neurochem 65:2800–2803.PubMedCrossRefGoogle Scholar
  56. Ginsberg SD, Rothstein JD, Price DL, Martin LJ (1996) Fimbria-fornix transections selectively down-regulate subtypes of glutamate transporter and glutamate receptor proteins in septum and hippocampus. J Neurochem 67:1208–1216.PubMedCrossRefGoogle Scholar
  57. Gomeza J, Hulsmann S, Ohno K, Eulenburg V, Szoke K, Richter D, Betz H (2003a) Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition. Neuron 40:785–796.CrossRefGoogle Scholar
  58. Gomeza J, Ohno K, Hulsmann S, Armsen W, Eulenburg V, Richter DW, Laube B, Betz H (2003b) Deletion of the mouse glycine transporter 2 results in a hyperekplexia phenotype and postnatal lethality. Neuron 40:797–806.CrossRefGoogle Scholar
  59. Gonzalez MI, Lopez-Colom AM, Ortega A (1999) Sodium-dependent glutamate transport in Muller glial cells: regulation by phorbol esters. Brain Res 831:140–145.PubMedCrossRefGoogle Scholar
  60. Grewer C, Rauen T (2005) Electrogenic glutamate transporters in the CNS: molecular mechanism, pre-steady-state kinetics, and their impact on synaptic signaling. J Membr Biol 203:1–20.PubMedCrossRefGoogle Scholar
  61. Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI (1990) Cloning and expression of a rat brain GABA transporter. Science 249:1303–1306.PubMedCrossRefGoogle Scholar
  62. Guo H, Lai L, Butchbach ME, Lin CL (2002) Human glioma cells and undifferentiated primary astrocytes that express aberrant EAAT2 mRNA inhibit normal EAAT2 protein expression and prevent cell death. Mol Cell Neurosci 21:546–560.PubMedCrossRefGoogle Scholar
  63. Guo H, Lai L, Butchbach ME, Stockinger MP, Shan X, Bishop GA, Lin CL (2003) Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 12:2519–2532.PubMedCrossRefGoogle Scholar
  64. Hamberger A, Nystrom B (1984) Extra- and intracellular amino acids in the hippocampus during development of hepatic encephalopathy. Neurochem Res 9:1181–1192.PubMedCrossRefGoogle Scholar
  65. Haugeto O, Ullensvang K, Levy LM, Chaudhry FA, Honore T, Nielsen M, Lehre KP, Danbolt NC (1996) Brain glutamate transporter proteins form homomultimers. J Biol Chem 271:27715–27722.PubMedCrossRefGoogle Scholar
  66. Hazell AS, Itzhak Y, Liu H, Norenberg MD (1997) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreases glutamate uptake in cultured astrocytes. J Neurochem 68:2216–2219.PubMedCrossRefGoogle Scholar
  67. He Y, Hof PR, Janssen WG, Rothstein JD, Morrison JH (2001) Differential synaptic localization of GluR2 and EAAC1 in the macaque monkey entorhinal cortex: a postembedding immunogold study. Neurosci Lett 311:161–164.PubMedCrossRefGoogle Scholar
  68. Headley PM, Grillner S (1990) Excitatory amino acids and synaptic transmission: the evidence for a physiological function. Trends Pharmacol Sci 11:205–211.PubMedCrossRefGoogle Scholar
  69. Heintz N (2001) BAC to the future: the use of bac transgenic mice for neuroscience research. Nat Rev Neurosci 2:861–870.PubMedCrossRefGoogle Scholar
  70. Herman MA, Jahr CE (2007) Extracellular glutamate concentration in hippocampal slice. J Neurosci 27:9736–9741.PubMedCrossRefGoogle Scholar
  71. Hertz L, Dringen R, Schousboe A, Robinson SR (1999) Astrocytes: glutamate producers for neurons. J Neurosci Res 57:417–428.PubMedCrossRefGoogle Scholar
  72. Honig LS, Chambliss DD, Bigio EH, Carroll SL, Elliott JL (2000) Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls. Neurology 55:1082–1088.PubMedGoogle Scholar
  73. Huang YH, Bergles DE (2004) Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol 14:346–352.PubMedCrossRefGoogle Scholar
  74. Huang YH, Sinha SR, Tanaka K, Rothstein JD, Bergles DE (2004) Astrocyte glutamate transporters regulate metabotropic glutamate receptor-mediated excitation of hippocampal interneurons. J Neurosci 24:4551–4559.PubMedCrossRefGoogle Scholar
  75. Hubner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ (2001) Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron 30:515–524.PubMedCrossRefGoogle Scholar
  76. Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grunblatt E (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11:97–116.PubMedGoogle Scholar
  77. Ji F, Obata K (1999) Development of the GABA system in organotypic culture of hippocampal and cerebellar slices from a 67-kDa isoform of glutamic acid decarboxylase (GAD67)-deficient mice. Neurosci Res 33:233–237.PubMedCrossRefGoogle Scholar
  78. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531.PubMedCrossRefGoogle Scholar
  79. Jursky F, Nelson N (1995) Localization of glycine neurotransmitter transporter (GLYT2) reveals correlation with the distribution of glycine receptor. J Neurochem 64:1026–1033.PubMedCrossRefGoogle Scholar
  80. Jursky F, Nelson N (1996) Developmental expression of the glycine transporters GLYT1 and GLYT2 in mouse brain. J Neurochem 67:336–344.PubMedCrossRefGoogle Scholar
  81. Kalandadze A, Wu Y, Robinson MB (2002) Protein kinase C activation decreases cell surface expression of the GLT-1 subtype of glutamate transporter. Requirement of a carboxyl-terminal domain and partial dependence on serine 486.J Biol Chem 277:45741–45750.PubMedCrossRefGoogle Scholar
  82. Kalandadze A, Wu Y, Fournier K, Robinson MB (2004) Identification of motifs involved in endoplasmic reticulum retention-forward trafficking of the GLT-1 subtype of glutamate transporter. J Neurosci 24:5183–5192.PubMedCrossRefGoogle Scholar
  83. Kam K, Nicoll R (2007) Excitatory synaptic transmission persists independently of glutamate–glutamine cycle. J Neurosci 27: 9192–9200.PubMedCrossRefGoogle Scholar
  84. Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471.PubMedCrossRefGoogle Scholar
  85. Kanai Y, Hediger MA (2004) The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. Pflugers Arch 447:469–479.PubMedCrossRefGoogle Scholar
  86. Kapetanovic IM, Yonekawa WD, Kupferberg HJ (1993) Time-related loss of glutamine from hippocampal slices and concomitant changes in neurotransmitter amino acids. J Neurochem 61:865–872.PubMedCrossRefGoogle Scholar
  87. Kim SY, Choi SY, Chao W, Volsky DJ (2003) Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes. J Neurochem 87:1485–1498.PubMedCrossRefGoogle Scholar
  88. Kojima S, Nakamura T, Nidaira T, Nakamura K, Ooashi N, Ito E, Watase K, Tanaka K, Wada K, Kudo Y, Miyakawa H (1999) Optical detection of synaptically induced glutamate transport in hippocampal slices. J Neurosci 19:2580–2588.PubMedGoogle Scholar
  89. Lauriat TL, Richler E, McInnes LA (2007) A quantitative regional expression profile of EAAT2 known and novel splice variants reopens the question of aberrant EAAT2 splicing in disease. Neurochem Int 50:271–280.PubMedCrossRefGoogle Scholar
  90. Lehre KP, Danbolt NC (1998) The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 18:8751–8757.PubMedGoogle Scholar
  91. Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (1995) Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 15:1835–1853.PubMedGoogle Scholar
  92. Levy LM, Warr O, Attwell D (1998) Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+-dependent glutamate uptake. J Neurosci 18:9620–9628.PubMedGoogle Scholar
  93. Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates GP (2001) Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8:807–821.PubMedCrossRefGoogle Scholar
  94. Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20:589–602.PubMedCrossRefGoogle Scholar
  95. Liu QR, Lopez-Corcuera B, Mandiyan S, Nelson H, Nelson N (1993) Molecular characterization of four pharmacologically distinct γ-aminobutyric acid transporters in mouse brain [corrected]. J Biol Chem 268:2106–2112.PubMedGoogle Scholar
  96. Lopez-Redondo F, Nakajima K, Honda S, Kohsaka S (2000) Glutamate transporter GLT-1 is highly expressed in activated microglia following facial nerve axotomy. Brain Res 76:429–435.CrossRefGoogle Scholar
  97. Macnab LT, Pow DV (2007) Central nervous system expression of the exon 9 skipping form of the glutamate transporter GLAST. Neuroreport 18:741–745.PubMedCrossRefGoogle Scholar
  98. Macnab LT, Williams SM, Pow DV (2006) Expression of the exon 3 skipping form of GLAST, GLAST1a, in brain and retina. Neuroreport 17:1867–1870.PubMedCrossRefGoogle Scholar
  99. Mahendrasingam S, Wallam CA, Hackney CM (2003) Two approaches to double post-embedding immunogold labeling of freeze-substituted tissue embedded in low temperature Lowicryl HM20 resin. Brain Res Brain Res Protoc 11:134–141.PubMedCrossRefGoogle Scholar
  100. Mallolas J, Hurtado O, Castellanos M, Blanco M, Sobrino T, Serena J, Vivancos J, Castillo J, Lizasoain I, Moro MA, Davalos A (2006) A polymorphism in the EAAT2 promoter is associated with higher glutamate concentrations and higher frequency of progressing stroke. J Exp Med 203:711–717.PubMedCrossRefGoogle Scholar
  101. Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates GP (1997) Instability of highly expanded CAG repeats in mice transgenic for the Huntington’s disease mutation. Nat Genet 15:197–200.PubMedCrossRefGoogle Scholar
  102. Maragakis NJ, Rothstein JD (2004) Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 15:461–473.PubMedCrossRefGoogle Scholar
  103. Martin LJ, Brambrink AM, Lehmann C, Portera-Cailliau C, Koehler R, Rothstein J, Traystman RJ (1997) Hypoxia–ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. Ann Neurol 42:335–348.PubMedCrossRefGoogle Scholar
  104. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40:759–766.PubMedCrossRefGoogle Scholar
  105. Masliah E, Alford M, Mallory M, Rockenstein E, Moechars D, Van Leuven F (2000) Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice. Exp Neurol 163:381–387.PubMedCrossRefGoogle Scholar
  106. Matsugami TR, Tanemura K, Mieda M, Nakatomi R, Yamada K, Kondo T, Ogawa M, Obata K, Watanabe M, Hashikawa T, Tanaka K (2006) From the cover: indispensability of the glutamate transporters GLAST and GLT1 to brain development. Proc Natl Acad Sci USA 103:12161–12166.PubMedCrossRefGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. McNaught KS, Jenner P (1999) Altered glial function causes neuronal death and increases neuronal susceptibility to 1-methyl-4-phenylpyridinium- and 6-hydroxydopamine-induced toxicity in astrocytic/ventral mesencephalic co-cultures. J Neurochem 73:2469–2476.PubMedCrossRefGoogle Scholar
  109. Munch C, Ebstein M, Seefried U, Zhu B, Stamm S, Landwehrmeyer GB, Ludolph AC, Schwalenstocker B, Meyer T (2002) Alternative splicing of the 5′-sequences of the mouse EAAT2 glutamate transporter and expression in a transgenic model for amyotrophic lateral sclerosis. J Neurochem 82:594–603.PubMedCrossRefGoogle Scholar
  110. Nagai M, Abe K, Okamoto K, Itoyama Y (1998) Identification of alternative splicing forms of GLT-1 mRNA in the spinal cord of amyotrophic lateral sclerosis patients. Neurosci Lett 244:165–168.PubMedCrossRefGoogle Scholar
  111. Nelson H, Mandiyan S, Nelson N (1990) Cloning of the human brain GABA transporter. FEBS Lett 269:181–184.PubMedCrossRefGoogle Scholar
  112. Nong Y, Huang YQ, Ju W, Kalia LV, Ahmadian G, Wang YT, Salter MW (2003) Glycine binding primes NMDA receptor internalization. Nature 422:302–307.PubMedCrossRefGoogle Scholar
  113. Pawlak J, Brito V, Kuppers E, Beyer C (2005) Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen. Brain Res 138:1–7.CrossRefGoogle Scholar
  114. Petroff OA (2002) GABA and glutamate in the human brain. Neuroscientist 8:562–573.PubMedCrossRefGoogle Scholar
  115. Pines G, Danbolt NC, Bjoras M, Zhang Y, Bendahan A, Eide L, Koepsell H, Storm-Mathisen J, Seeberg E, Kanner BI (1992) Cloning and expression of a rat brain l. -glutamate transporter Nature 360:464–467.PubMedCrossRefGoogle Scholar
  116. Plachez C, Danbolt NC, Recasens M (2000) Transient expression of the glial glutamate transporters GLAST and GLT in hippocampal neurons in primary culture. J Neurosci Res 59:587–593.PubMedCrossRefGoogle Scholar
  117. Poitry-Yamate CL, Vutskits L, Rauen T (2002) Neuronal-induced and glutamate-dependent activation of glial glutamate transporter function. J Neurochem 82:987–997.PubMedCrossRefGoogle Scholar
  118. Pow DV, Hendrickson AE (1999) Distribution of the glycine transporter glyt-1 in mammalian and nonmammalian retinae. Vis Neurosci 16:231–239.PubMedCrossRefGoogle Scholar
  119. Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen O, Gispen WH, de Graan PN (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43.PubMedCrossRefGoogle Scholar
  120. Rauen T (2000) Diversity of glutamate transporter expression and function in the mammalian retina. Amino Acids 19:53–62.PubMedCrossRefGoogle Scholar
  121. Rauen T, Fischer F, Wiessner M (1999) Glia–neuron interaction by high-affinity glutamate transporters in neurotransmission. Adv Exp Med Biol 468:81–95.PubMedGoogle Scholar
  122. Rauen T, Wiessner M, Sullivan R, Lee A, Pow DV (2004) A new GLT1 splice variant: cloning and immunolocalization of GLT1c in the mammalian retina and brain. Neurochem Int 45:1095–1106.PubMedCrossRefGoogle Scholar
  123. Regan MR, Huang YH, Kim YS, Dykes-Hoberg MI, Jin L, Watkins AM, Bergles DE, Rothstein JD (2007) Variations in promoter activity reveal a differential expression and physiology of glutamate transporters by glia in the developing and mature CNS. J Neurosci 27:6607–6619.PubMedCrossRefGoogle Scholar
  124. Reichelt W, Knopfel T (2002) Glutamate uptake controls expression of a slow postsynaptic current mediated by mGluRs in cerebellar Purkinje cells. J Neurophysiol 87:1974–1980.PubMedGoogle Scholar
  125. Robinson MB (2006) Acute regulation of sodium-dependent glutamate transporters: a focus on constitutive and regulated trafficking. Handb Exp Pharmacol:251–275.Google Scholar
  126. Rosas S, Vargas MA, Lopez-Bayghen E, Ortega A (2007) Glutamate-dependent transcriptional regulation of GLAST/EAAT1: a role for YY1. J Neurochem 101:1134–1144.PubMedCrossRefGoogle Scholar
  127. Rose CR, Ransom BR (1996a) Mechanisms of H+ and Na+ changes induced by glutamate, kainate, and d. -aspartate in rat hippocampal astrocytes J Neurosci 16:5393–5404.Google Scholar
  128. Rose CR, Ransom BR (1996b) Intracellular sodium homeostasis in rat hippocampal astrocytes. J Physiol 491 (Pt 2):291–305.Google Scholar
  129. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62.PubMedCrossRefGoogle Scholar
  130. Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468.PubMedCrossRefGoogle Scholar
  131. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW (1994) Localization of neuronal and glial glutamate transporters. Neuron 13:713–725.PubMedCrossRefGoogle Scholar
  132. Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84.PubMedCrossRefGoogle Scholar
  133. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686.PubMedCrossRefGoogle Scholar
  134. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77.PubMedCrossRefGoogle Scholar
  135. Rozyczka J, Engele J (2005) Multiple 5′-splice variants of the rat glutamate transporter-1. Brain Res 133:157–161.CrossRefGoogle Scholar
  136. Rudolph U, Mohler H (2006) GABA-based therapeutic approaches: GABAA. receptor subtype functions Curr Opin Pharmacol 6:18–23.PubMedCrossRefGoogle Scholar
  137. Sattler R, Tymianski M (2001) Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol 24:107–129.PubMedCrossRefGoogle Scholar
  138. Sattler R, Rothstein JD (2006) Regulation and dysregulation of glutamate transporters. Handb Exp Pharmacol:277–303.Google Scholar
  139. Schlag BD, Vondrasek JR, Munir M, Kalandadze A, Zelenaia OA, Rothstein JD, Robinson MB (1998) Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol Pharmacol 53:355–369.PubMedGoogle Scholar
  140. Schmitt A, Asan E, Puschel B, Jons T, Kugler P (1996) Expression of the glutamate transporter GLT1 in neural cells of the rat central nervous system: non-radioactive in situ hybridization and comparative immunocytochemistry. Neuroscience 71:989–1004.PubMedCrossRefGoogle Scholar
  141. Schousboe A (2000) Pharmacological and functional characterization of astrocytic GABA transport: a short review. Neurochem Res 25:1241–1244.PubMedCrossRefGoogle Scholar
  142. Schousboe A (2003) Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission. Neurochem Res 28:347–352.PubMedCrossRefGoogle Scholar
  143. Schousboe A, Hertz L (1981) Role of astroglial cells in glutamate homeostasis. Adv Biochem Psychopharmacol 27:103–113.PubMedGoogle Scholar
  144. Scott HL, Pow DV, Tannenberg AE, Dodd PR (2002) Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer’s disease. J Neurosci 22:RC206.PubMedGoogle Scholar
  145. Seal RP, Amara SG (1999) Excitatory amino acid transporters: a family in flux. Annu Rev Pharmacol Toxicol 39:431–456.PubMedCrossRefGoogle Scholar
  146. Sheldon AL, Robinson MB (2007) The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int.551:333–355CrossRefGoogle Scholar
  147. Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ (2005) Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 171:1001–1012.PubMedCrossRefGoogle Scholar
  148. Sitcheran R, Gupta P, Fisher PB, Baldwin AS (2005) Positive and negative regulation of EAAT2 by NF-κB: a role for N-myc in TNFα-controlled repression. EMBO J 24:510–520.PubMedCrossRefGoogle Scholar
  149. Soghomonian JJ, Martin DL (1998) Two isoforms of glutamate decarboxylase: why? Trends Pharmacol Sci : 19500–505.CrossRefGoogle Scholar
  150. Sonders MS, Amara SG (1996) Channels in transporters. Curr Opin Neurobiol 6:294–302.PubMedCrossRefGoogle Scholar
  151. Storck T, Schulte S, Hofmann K, Stoffel W (1992) Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc Natl Acad Sci USA 89:10955–10959.PubMedCrossRefGoogle Scholar
  152. Su ZZ, Leszczyniecka M, Kang DC, Sarkar D, Chao W, Volsky DJ, Fisher PB (2003) Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2). Proc Natl Acad Sci USA 100:1955–1960.PubMedCrossRefGoogle Scholar
  153. Sudhof TC (1995) The synaptic vesicle cycle: a cascade of protein–protein interactions. Nature 375:645–653.PubMedCrossRefGoogle Scholar
  154. Sutherland ML, Delaney TA, Noebels JL (1996) Glutamate transporter mRNA expression in proliferative zones of the developing and adult murine CNS. J Neurosci 16:2191–2207.PubMedGoogle Scholar
  155. Suzdak PD, Jansen JA (1995) A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 36:612–626.PubMedCrossRefGoogle Scholar
  156. Swanson RA, Liu J, Miller JW, Rothstein JD, Farrell K, Stein BA, Longuemare MC (1997) Neuronal regulation of glutamate transporter subtype expression in astrocytes. J Neurosci 17:932–940.PubMedGoogle Scholar
  157. Takamori S, Rhee JS, Rosenmund C, Jahn R (2000) Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons. Nature 407:189–194.PubMedCrossRefGoogle Scholar
  158. Tanaka K (1993) Cloning and expression of a glutamate transporter from mouse brain. Neurosci Lett 159:183–186.PubMedCrossRefGoogle Scholar
  159. Tanaka K (1997) Epilepsy and exacerbation of brain injury in mice lacking glutamate transporter GLT-1. Science 276:1699 (278:21).PubMedCrossRefGoogle Scholar
  160. Tao F, Lu SD, Zhang LM, Huang YL, Sun FY (2001) Role of excitatory amino acid transporter 1 in neonatal rat neuronal damage induced by hypoxia–ischemia. Neuroscience 102:503–513.PubMedCrossRefGoogle Scholar
  161. Thai DR (2002) Excitatory amino acid transporter EAAT-2 in tangle-bearing neurons in Alzheimer’s disease. Brain Pathol 12:405–411.PubMedGoogle Scholar
  162. Tian G, Lai L, Guo H, Lin Y, Butchbach ME, Chang Y, Lin CL (2007) Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem 282:1727–1737.PubMedCrossRefGoogle Scholar
  163. Tong G, Jahr CE (1994) Block of glutamate transporters potentiates postsynaptic excitation. Neuron 13:1195–1203.PubMedCrossRefGoogle Scholar
  164. Torres GE, Amara SG (2007) Glutamate and monoamine transporters: new visions of form and function. Curr Opin Neurobiol 17:304–312.PubMedCrossRefGoogle Scholar
  165. Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13–25.PubMedCrossRefGoogle Scholar
  166. Trotti D, Rolfs A, Danbolt NC, Brown RH, Jr., Hediger MA (1999) SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci 2:427–433.PubMedCrossRefGoogle Scholar
  167. Vandenberg RJ (2006) Mutational analysis of glutamate transporters. Handb Exp Pharmacol:113–135.Google Scholar
  168. Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 19:6897–6906.PubMedGoogle Scholar
  169. Wadiche JI, Amara SG, Kavanaugh MP (1995) Ion fluxes associated with excitatory amino acid transport. Neuron 15:721–728.PubMedCrossRefGoogle Scholar
  170. Watanabe T, Morimoto K, Hirao T, Suwaki H, Watase K, Tanaka K (1999) Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. Brain Res 845:92–96.PubMedCrossRefGoogle Scholar
  171. Westergaard N, Sonnewald U, Schousboe A (1995) Metabolic trafficking between neurons and astrocytes: the glutamate/glutamine cycle revisited. Dev Neurosci 17:203–211.PubMedCrossRefGoogle Scholar
  172. Wood JH, Hare TA, Glaeser BS, Ballenger JC, Post RM (1979) Low cerebrospinal fluid γ-aminobutyric acid content in seizure patients. Neurology 29:1203–1208.PubMedGoogle Scholar
  173. Yamada H, Yatsushiro S, Yamamoto A, Hayashi M, Nishi T, Futai M, Yamaguchi A, Moriyama Y (1997) Functional expression of a GLT-1 type Na+-dependent glutamate transporter in rat pinealocytes. J Neurochem 69:1491–1498.PubMedCrossRefGoogle Scholar
  174. Yernool D, Boudker O, Jin Y, Gouaux E (2004) Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431:811–818.PubMedCrossRefGoogle Scholar
  175. Zelenaia O, Schlag BD, Gochenauer GE, Ganel R, Song W, Beesley JS, Grinspan JB, Rothstein JD, Robinson MB (2000) Epidermal growth factor receptor agonists increase expression of glutamate transporter GLT-1 in astrocytes through pathways dependent on phosphatidylinositol 3-kinase and transcription factor NF-κB. Mol Pharmacol 57:667–678.PubMedGoogle Scholar
  176. Zerangue N, Kavanaugh MP (1996) Flux coupling in a neuronal glutamate transporter. Nature 383:634–637.PubMedCrossRefGoogle Scholar
  177. Zhou J, Sutherland ML (2004) Glutamate transporter cluster formation in astrocytic processes regulates glutamate uptake activity. J Neurosci 24:6301–6306.PubMedCrossRefGoogle Scholar
  178. Zschocke J, Bayatti N, Clement AM, Witan H, Figiel M, Engele J, Behl C (2005) Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. J Biol Chem 280:34924–34932.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Yongjie Yang
  • Jeffrey D. Rothstein

There are no affiliations available

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