Advertisement

Cellular and Molecular Life Sciences

, Volume 72, Issue 18, pp 3489–3506 | Cite as

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

  • Kou Takahashi
  • Joshua B. Foster
  • Chien-Liang Glenn LinEmail author
Review

Abstract

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson’s disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.

Keywords

Glutamate transporters Astrocytes Neurodegenerative disease Glutamic acid GLT-1 Depression Ceftriaxone LDN/OSU-0212320 

Abbreviations

NF-kB

Nuclear factor kappa B

Sp1

Specificity protein 1

NFAT

Nuclear factor of activated T-cells

YY1

Yin Yang 1

EGF

Epidermal growth factor

TGF-alpha

Transforming growth factor alpha

EGR

Early growth response protein

Notes

Acknowledgments

This review article was supported by US National Institutes of Health grants R01NS064275 and U01NS074601, the BrightFocus Foundation, the Alzheimer’s Drug Discovery Foundation, and the Thome Memorial Foundation.

References

  1. 1.
    Beart PM, O’Shea RD (2007) Transporters for l-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150:5–17PubMedCentralPubMedGoogle Scholar
  2. 2.
    Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105PubMedGoogle Scholar
  3. 3.
    Grewer C et al (2014) SLC1 glutamate transporters. Pflugers Arch 466:3–24PubMedCentralPubMedGoogle Scholar
  4. 4.
    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 203:1–20PubMedCentralPubMedGoogle Scholar
  5. 5.
    Vandenberg RJ, Ryan RM (2013) Mechanisms of glutamate transport. Physiol Rev 93:1621–1657PubMedGoogle Scholar
  6. 6.
    Holmseth S et al (2012) The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32:6000–6013PubMedCentralPubMedGoogle Scholar
  7. 7.
    Rothstein JD et al (1994) Localization of neuronal and glial glutamate transporters. Neuron 13:713–725PubMedGoogle Scholar
  8. 8.
    Lehre KP et al (1995) Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 15:1835–1853PubMedGoogle Scholar
  9. 9.
    Dehnes Y et al (1998) The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci 18:3606–3619PubMedGoogle Scholar
  10. 10.
    Yamada K et al (1996) EAAT4 is a post-synaptic glutamate transporter at Purkinje cell synapses. Neuroreport 7:2013–2017PubMedGoogle Scholar
  11. 11.
    Arriza JL et al (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94:4155–4160PubMedCentralPubMedGoogle Scholar
  12. 12.
    Massie A et al (2008) High-affinity Na+/K+-dependent glutamate transporter EAAT4 is expressed throughout the rat fore- and midbrain. J Comp Neurol 511:155–172PubMedGoogle Scholar
  13. 13.
    Bjornsen LP et al (2014) The GLT-1 (EAAT2; slc1a2) glutamate transporter is essential for glutamate homeostasis in the neocortex of the mouse. J Neurochem 128:641–649PubMedGoogle Scholar
  14. 14.
    Rothstein JD et al (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686PubMedGoogle Scholar
  15. 15.
    Haugeto O et al (1996) Brain glutamate transporter proteins form homomultimers. J Biol Chem 271:27715–27722PubMedGoogle Scholar
  16. 16.
    Tanaka K et al (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702PubMedGoogle Scholar
  17. 17.
    Kim SY et al (2003) Cloning and characterization of the 3′-untranslated region of the human excitatory amino acid transporter 2 transcript. J Neurochem 86:1458–1467PubMedGoogle Scholar
  18. 18.
    Maragakis NJ et al (2004) Altered expression of the glutamate transporter EAAT2b in neurological disease. Ann Neurol 55:469–477PubMedGoogle Scholar
  19. 19.
    Bassan M et al (2008) Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1. Eur J Neurosci 27:66–82PubMedCentralPubMedGoogle Scholar
  20. 20.
    Sogaard R et al (2013) Functional modulation of the glutamate transporter variant GLT1b by the PDZ domain protein PICK1. J Biol Chem 288:20195–20207PubMedCentralPubMedGoogle Scholar
  21. 21.
    Chen W et al (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 22:2142–2152PubMedCentralPubMedGoogle Scholar
  22. 22.
    Chaudhry FA et al (1995) Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron 15:711–720PubMedGoogle Scholar
  23. 23.
    Furness DN et al (2008) A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2). Neuroscience 157:80–94PubMedCentralPubMedGoogle Scholar
  24. 24.
    Holmseth S et al (2009) The concentrations and distributions of three C-terminal variants of the GLT1 (EAAT2; slc1a2) glutamate transporter protein in rat brain tissue suggest differential regulation. Neuroscience 162:1055–1071PubMedGoogle Scholar
  25. 25.
    Kugler P, Schmitt A (2003) Complementary neuronal and glial expression of two high-affinity glutamate transporter GLT1/EAAT2 forms in rat cerebral cortex. Histochem Cell Biol 119:425–435PubMedGoogle Scholar
  26. 26.
    Schmitt A et al (2002) A splice variant of glutamate transporter GLT1/EAAT2 expressed in neurons: cloning and localization in rat nervous system. Neuroscience 109:45–61PubMedGoogle Scholar
  27. 27.
    Reye P et al (2002) Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary. Glia 38:246–255PubMedGoogle Scholar
  28. 28.
    Sullivan R et al (2004) Cloning, transport properties, and differential localization of two splice variants of GLT-1 in the rat CNS: implications for CNS glutamate homeostasis. Glia 45:155–169PubMedGoogle Scholar
  29. 29.
    Chen W et al (2004) The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J Neurosci 24:1136–1148PubMedCentralPubMedGoogle Scholar
  30. 30.
    Berger UV et al (2005) Cellular and subcellular mRNA localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ hybridization. J Comp Neurol 492:78–89PubMedCentralPubMedGoogle Scholar
  31. 31.
    Rauen T et al (2004) A new GLT1 splice variant: cloning and immunolocalization of GLT1c in the mammalian retina and brain. Neurochem Int 45:1095–1106PubMedGoogle Scholar
  32. 32.
    Figiel M, Engele J (2000) Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuron-derived peptide regulating glial glutamate transport and metabolism. J Neurosci 20:3596–3605PubMedGoogle Scholar
  33. 33.
    Karki P et al (2013) cAMP response element-binding protein (CREB) and nuclear factor kappaB mediate the tamoxifen-induced up-regulation of glutamate transporter 1 (GLT-1) in rat astrocytes. J Biol Chem 288:28975–28986PubMedCentralPubMedGoogle Scholar
  34. 34.
    Karki P et al (2014) Mechanism of raloxifene-induced upregulation of glutamate transporters in rat primary astrocytes. Glia 62:1270–1283PubMedCentralPubMedGoogle Scholar
  35. 35.
    Lee E et al (2012) GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. J Biol Chem 287:26817–26828PubMedCentralPubMedGoogle Scholar
  36. 36.
    Sitcheran R et al (2005) Positive and negative regulation of EAAT2 by NF-kappaB: a role for N-myc in TNFalpha-controlled repression. EMBO J 24:510–520PubMedCentralPubMedGoogle Scholar
  37. 37.
    Su ZZ et al (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 100:1955–1960PubMedCentralPubMedGoogle Scholar
  38. 38.
    Ghosh M et al (2011) Nuclear factor-kappaB contributes to neuron-dependent induction of glutamate transporter-1 expression in astrocytes. J Neurosci 31:9159–9169PubMedCentralPubMedGoogle Scholar
  39. 39.
    Zelenaia O et al (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-kappaB. Mol Pharmacol 57:667–678PubMedGoogle Scholar
  40. 40.
    Lee SG et al (2008) Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem 283:13116–13123PubMedCentralPubMedGoogle Scholar
  41. 41.
    Rothstein JD et al (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77PubMedGoogle Scholar
  42. 42.
    Gegelashvili G et al (1997) Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia. J Neurochem 69:2612–2615PubMedGoogle Scholar
  43. 43.
    Schlag BD et al (1998) Regulation of the glial Na+-dependent glutamate transporters by cyclic AMP analogs and neurons. Mol Pharmacol 53:355–369PubMedGoogle Scholar
  44. 44.
    Yang Y et al (2009) Presynaptic regulation of astroglial excitatory neurotransmitter transporter GLT1. Neuron 61:880–894PubMedCentralPubMedGoogle Scholar
  45. 45.
    Fumagalli E et al (2008) Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol 578:171–176PubMedGoogle Scholar
  46. 46.
    Liu AY et al (2011) Neuroprotective drug riluzole amplifies the heat shock factor 1 (HSF1)- and glutamate transporter 1 (GLT1)-dependent cytoprotective mechanisms for neuronal survival. J Biol Chem 286:2785–2794PubMedCentralPubMedGoogle Scholar
  47. 47.
    Perisic T et al (2010) Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes. Neuropsychopharmacology 35:792–805PubMedCentralPubMedGoogle Scholar
  48. 48.
    Karki P et al (2014) Yin Yang 1 is a repressor of glutamate transporter EAAT2, and it mediates manganese-induced decrease of EAAT2 expression in astrocytes. Mol Cell Biol 34:1280–1289PubMedCentralPubMedGoogle Scholar
  49. 49.
    Perisic T et al (2012) The CpG island shore of the GLT-1 gene acts as a methylation-sensitive enhancer. Glia 60:1345–1355PubMedGoogle Scholar
  50. 50.
    Yang Y et al (2010) Epigenetic regulation of neuron-dependent induction of astroglial synaptic protein GLT1. Glia 58:277–286PubMedCentralPubMedGoogle Scholar
  51. 51.
    Tian G et al (2007) Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem 282:1727–1737PubMedGoogle Scholar
  52. 52.
    Morel L et al (2013) Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem 288:7105–7116PubMedCentralPubMedGoogle Scholar
  53. 53.
    Carmona MA et al (2009) Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proc Natl Acad Sci USA 106:12524–12529PubMedCentralPubMedGoogle Scholar
  54. 54.
    Filosa A et al (2009) Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nat Neurosci 12:1285–1292PubMedCentralPubMedGoogle Scholar
  55. 55.
    Colton CK et al (2010) Identification of translational activators of glial glutamate transporter EAAT2 through cell-based high-throughput screening: an approach to prevent excitotoxicity. J Biomol Screen 15:653–662PubMedCentralPubMedGoogle Scholar
  56. 56.
    Kong Q et al (2014) Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection. J Clin Invest 124:1255–1267PubMedCentralPubMedGoogle Scholar
  57. 57.
    Xing X et al (2011) Structure-activity relationship study of pyridazine derivatives as glutamate transporter EAAT2 activators. Bioorg Med Chem Lett 21:5774–5777PubMedCentralPubMedGoogle Scholar
  58. 58.
    Huang K et al (2010) Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease. Neurobiol Dis 40:207–215PubMedGoogle Scholar
  59. 59.
    Foran E et al (2014) Sumoylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization. Glia 62:1241–1253PubMedCentralPubMedGoogle Scholar
  60. 60.
    Garcia-Tardon N et al (2012) Protein kinase C (PKC)-promoted endocytosis of glutamate transporter GLT-1 requires ubiquitin ligase Nedd4-2-dependent ubiquitination but not phosphorylation. J Biol Chem 287:19177–19187PubMedCentralPubMedGoogle Scholar
  61. 61.
    Gonzalez-Gonzalez IM et al (2008) PKC-dependent endocytosis of the GLT1 glutamate transporter depends on ubiquitylation of lysines located in a C-terminal cluster. Glia 56:963–974PubMedGoogle Scholar
  62. 62.
    Sheldon AL et al (2008) Ubiquitination-mediated internalization and degradation of the astroglial glutamate transporter, GLT-1. Neurochem Int 53:296–308PubMedCentralPubMedGoogle Scholar
  63. 63.
    Tian G et al (2010) Increased expression of cholesterol 24S-hydroxylase results in disruption of glial glutamate transporter EAAT2 association with lipid rafts: a potential role in Alzheimer’s disease. J Neurochem 113:978–989PubMedCentralPubMedGoogle Scholar
  64. 64.
    Benediktsson AM et al (2012) Neuronal activity regulates glutamate transporter dynamics in developing astrocytes. Glia 60:175–188PubMedCentralPubMedGoogle Scholar
  65. 65.
    Poitry-Yamate CL et al (2002) Neuronal-induced and glutamate-dependent activation of glial glutamate transporter function. J Neurochem 82:987–997PubMedGoogle Scholar
  66. 66.
    Fontana AC et al (2007) Enhancing glutamate transport: mechanism of action of Parawixin1, a neuroprotective compound from Parawixia bistriata spider venom. Mol Pharmacol 72:1228–1237PubMedGoogle Scholar
  67. 67.
    Fontana AC et al (2003) Purification of a neuroprotective component of Parawixia bistriata spider venom that enhances glutamate uptake. Br J Pharmacol 139:1297–1309PubMedCentralPubMedGoogle Scholar
  68. 68.
    Bridges RJ, Esslinger CS (2005) The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol Ther 107:271–285PubMedGoogle Scholar
  69. 69.
    Bunch L et al (2009) Excitatory amino acid transporters as potential drug targets. Expert Opin Ther Targets 13:719–731PubMedGoogle Scholar
  70. 70.
    Arriza JL et al (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14:5559–5569PubMedGoogle Scholar
  71. 71.
    Fairman WA et al (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375:599–603PubMedGoogle Scholar
  72. 72.
    Griffiths R et al (1994) l-Trans-pyrrolidine-2,4-dicarboxylate and cis-1-aminocyclobutane-1,3-dicarboxylate behave as transportable, competitive inhibitors of the high-affinity glutamate transporters. Biochem Pharmacol 47:267–274PubMedGoogle Scholar
  73. 73.
    Rauen T et al (1992) Comparative analysis of sodium-dependent l-glutamate transport of synaptosomal and astroglial membrane vesicles from mouse cortex. FEBS Lett 312:15–20PubMedGoogle Scholar
  74. 74.
    Shimamoto K et al (1998) dl-Threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. Mol Pharmacol 53:195–201PubMedGoogle Scholar
  75. 75.
    Shimamoto K et al (2004) Characterization of novel L-threo-beta-benzyloxyaspartate derivatives, potent blockers of the glutamate transporters. Mol Pharmacol 65:1008–1015PubMedGoogle Scholar
  76. 76.
    Dunlop J et al (2005) Characterization of novel aryl-ether, biaryl, and fluorene aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinity glutamate transporter EAAT2. Mol Pharmacol 68:974–982PubMedGoogle Scholar
  77. 77.
    Greenfield A et al (2005) Synthesis and biological activities of aryl-ether-, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinity glutamate transporter EAAT-2. Bioorg Med Chem Lett 15:4985–4988PubMedGoogle Scholar
  78. 78.
    Callender R et al (2012) Mechanism of inhibition of the glutamate transporter EAAC1 by the conformationally constrained glutamate analogue (+)-HIP-B. Biochemistry 51:5486–5495PubMedCentralPubMedGoogle Scholar
  79. 79.
    Colleoni S et al (2008) Neuroprotective effects of the novel glutamate transporter inhibitor (-)-3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylic acid, which preferentially inhibits reverse transport (glutamate release) compared with glutamate reuptake. J Pharmacol Exp Ther 326:646–656PubMedGoogle Scholar
  80. 80.
    Abrahamsen B et al (2013) Allosteric modulation of an excitatory amino acid transporter: the subtype-selective inhibitor UCPH-101 exerts sustained inhibition of EAAT1 through an intramonomeric site in the trimerization domain. J Neurosci 33:1068–1087PubMedGoogle Scholar
  81. 81.
    Erichsen MN et al (2010) Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chrom ene-3-carbonitrile (UCPH-101). J Med Chem 53:7180–7191PubMedGoogle Scholar
  82. 82.
    Jensen AA et al (2009) Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1. J Med Chem 52:912–915PubMedGoogle Scholar
  83. 83.
    Jiang J, Amara SG (2011) New views of glutamate transporter structure and function: advances and challenges. Neuropharmacology 60:172–181PubMedCentralPubMedGoogle Scholar
  84. 84.
    Boudker O et al (2007) Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter. Nature 445:387–393PubMedGoogle Scholar
  85. 85.
    Reyes N et al (2009) Transport mechanism of a bacterial homologue of glutamate transporters. Nature 462:880–885PubMedCentralPubMedGoogle Scholar
  86. 86.
    Yernool D et al (2004) Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431:811–818PubMedGoogle Scholar
  87. 87.
    Gendreau S et al (2004) A trimeric quaternary structure is conserved in bacterial and human glutamate transporters. J Biol Chem 279:39505–39512PubMedGoogle Scholar
  88. 88.
    Nothmann D et al (2011) Hetero-oligomerization of neuronal glutamate transporters. J Biol Chem 286:3935–3943PubMedCentralPubMedGoogle Scholar
  89. 89.
    Danbolt NC et al (1992) An [Na+ + K+]coupled L-glutamate transporter purified from rat brain is located in glial cell processes. Neuroscience 51:295–310PubMedGoogle Scholar
  90. 90.
    Herman MA, Jahr CE (2007) Extracellular glutamate concentration in hippocampal slice. J Neurosci 27:9736–9741PubMedCentralPubMedGoogle Scholar
  91. 91.
    Otis TS, Jahr CE (1998) Anion currents and predicted glutamate flux through a neuronal glutamate transporter. J Neurosci 18:7099–7110PubMedGoogle Scholar
  92. 92.
    Tong G, Jahr CE (1994) Block of glutamate transporters potentiates postsynaptic excitation. Neuron 13:1195–1203PubMedGoogle Scholar
  93. 93.
    Wadiche JI, Kavanaugh MP (1998) Macroscopic and microscopic properties of a cloned glutamate transporter/chloride channel. J Neurosci 18:7650–7661PubMedGoogle Scholar
  94. 94.
    Diamond JS, Jahr CE (1997) Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci 17:4672–4687PubMedGoogle Scholar
  95. 95.
    Otis TS, Kavanaugh MP (2000) Isolation of current components and partial reaction cycles in the glial glutamate transporter EAAT2. J Neurosci 20:2749–2757PubMedGoogle Scholar
  96. 96.
    Tzingounis AV, Wadiche JI (2007) Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 8:935–947PubMedGoogle Scholar
  97. 97.
    Wadiche JI et al (1995) Kinetics of a human glutamate transporter. Neuron 14:1019–1027PubMedGoogle Scholar
  98. 98.
    Lozovaya NA et al (1999) Enhancement of glutamate release uncovers spillover-mediated transmission by N-methyl-d-aspartate receptors in the rat hippocampus. Neuroscience 91:1321–1330PubMedGoogle Scholar
  99. 99.
    Pita-Almenar JD et al (2012) Relationship between increase in astrocytic GLT-1 glutamate transport and late-LTP. Learn Mem 19:615–626PubMedCentralPubMedGoogle Scholar
  100. 100.
    Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682–696PubMedCentralPubMedGoogle Scholar
  101. 101.
    Parsons MP, Raymond LA (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 82:279–293PubMedGoogle Scholar
  102. 102.
    Lai TW et al (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188PubMedGoogle Scholar
  103. 103.
    Hertz L (1979) Functional interactions between neurons and astrocytes I. Turnover and metabolism of putative amino acid transmitters. Prog Neurobiol 13:277–323PubMedGoogle Scholar
  104. 104.
    van den Berg CJ, Garfinkel D (1971) A stimulation study of brain compartments. Metabolism of glutamate and related substances in mouse brain. Biochem J 123:211–218PubMedGoogle Scholar
  105. 105.
    Kam K, Nicoll R (2007) Excitatory synaptic transmission persists independently of the glutamate–glutamine cycle. J Neurosci 27:9192–9200PubMedGoogle Scholar
  106. 106.
    Tani H et al (2014) A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron 81:888–900PubMedCentralPubMedGoogle Scholar
  107. 107.
    McKenna MC (2013) Glutamate pays its own way in astrocytes. Front Endocrinol (Lausanne) 4:191Google Scholar
  108. 108.
    Hertz L, Hertz E (2003) Cataplerotic TCA cycle flux determined as glutamate-sustained oxygen consumption in primary cultures of astrocytes. Neurochem Int 43:355–361PubMedGoogle Scholar
  109. 109.
    McKenna MC (2012) Substrate competition studies demonstrate oxidative metabolism of glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate in cortical astrocytes from rat brain. Neurochem Res 37:2613–2626PubMedCentralPubMedGoogle Scholar
  110. 110.
    Sonnewald U et al (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 61:1179–1182PubMedGoogle Scholar
  111. 111.
    Genda EN et al (2011) Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J Neurosci 31:18275–18288PubMedCentralPubMedGoogle Scholar
  112. 112.
    Grewer C et al (2008) Glutamate forward and reverse transport: from molecular mechanism to transporter-mediated release after ischemia. IUBMB Life 60:609–619PubMedCentralPubMedGoogle Scholar
  113. 113.
    Szatkowski M et al (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348:443–446PubMedGoogle Scholar
  114. 114.
    Rossi DJ et al (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403:316–321PubMedGoogle Scholar
  115. 115.
    Petralia RS et al (2010) Organization of NMDA receptors at extrasynaptic locations. Neuroscience 167:68–87PubMedCentralPubMedGoogle Scholar
  116. 116.
    Gouix E et al (2009) Reverse glial glutamate uptake triggers neuronal cell death through extrasynaptic NMDA receptor activation. Mol Cell Neurosci 40:463–473PubMedGoogle Scholar
  117. 117.
    Blitzblau R et al (1996) The glutamate transport inhibitor l-trans-pyrrolidine-2,4-dicarboxylate indirectly evokes NMDA receptor mediated neurotoxicity in rat cortical cultures. Eur J Neurosci 8:1840–1852PubMedGoogle Scholar
  118. 118.
    Volterra A et al (1996) The competitive transport inhibitor l-trans-pyrrolidine-2, 4-dicarboxylate triggers excitotoxicity in rat cortical neuron-astrocyte co-cultures via glutamate release rather than uptake inhibition. Eur J Neurosci 8:2019–2028PubMedGoogle Scholar
  119. 119.
    Zhou Y et al (2014) EAAT2 (GLT-1; slc1a2) glutamate transporters reconstituted in liposomes argues against heteroexchange being substantially faster than net uptake. J Neurosci 34:13472–13485PubMedCentralPubMedGoogle Scholar
  120. 120.
    Billups B et al (1996) Anion conductance behavior of the glutamate uptake carrier in salamander retinal glial cells. J Neurosci 16:6722–6731PubMedGoogle Scholar
  121. 121.
    Grewer C et al (2000) Glutamate translocation of the neuronal glutamate transporter EAAC1 occurs within milliseconds. Proc Natl Acad Sci USA 97:9706–9711PubMedCentralPubMedGoogle Scholar
  122. 122.
    Mim C et al (2005) The glutamate transporter subtypes EAAT4 and EAATs 1-3 transport glutamate with dramatically different kinetics and voltage dependence but share a common uptake mechanism. J Gen Physiol 126:571–589PubMedCentralPubMedGoogle Scholar
  123. 123.
    Gameiro A et al (2011) The discovery of slowness: low-capacity transport and slow anion channel gating by the glutamate transporter EAAT5. Biophys J 100:2623–2632PubMedCentralPubMedGoogle Scholar
  124. 124.
    Veruki ML et al (2006) Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nat Neurosci 9:1388–1396PubMedGoogle Scholar
  125. 125.
    Lozano R et al (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2095–2128PubMedGoogle Scholar
  126. 126.
    Murray CJ et al (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2197–2223PubMedGoogle Scholar
  127. 127.
    Donnan GA et al (2008) Stroke. Lancet 371:1612–1623PubMedGoogle Scholar
  128. 128.
    Brown AM et al (2004) Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochem Int 45:529–536PubMedGoogle Scholar
  129. 129.
    Dawson LA et al (2000) Characterization of transient focal ischemia-induced increases in extracellular glutamate and aspartate in spontaneously hypertensive rats. Brain Res Bull 53:767–776PubMedGoogle Scholar
  130. 130.
    Mitani A et al (1990) Gerbil hippocampal extracellular glutamate and neuronal activity after transient ischemia. Brain Res Bull 25:319–324PubMedGoogle Scholar
  131. 131.
    Globus MY et al (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 51:1455–1464PubMedGoogle Scholar
  132. 132.
    Hagberg H et al (1985) Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. J Cereb Blood Flow Metab 5:413–419PubMedGoogle Scholar
  133. 133.
    Drejer J et al (1985) Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro. J Neurochem 45:145–151PubMedGoogle Scholar
  134. 134.
    Benveniste H et al (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374PubMedGoogle Scholar
  135. 135.
    Weller ML et al (2008) Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience 155:1204–1211PubMedCentralPubMedGoogle Scholar
  136. 136.
    Chu K et al (2007) Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke 38:177–182PubMedGoogle Scholar
  137. 137.
    Hu YY et al (2015) Ceftriaxone modulates uptake activity of glial glutamate transporter-1 against global brain ischemia in rats. J Neurochem 132:194–205PubMedGoogle Scholar
  138. 138.
    Inui T et al (2013) Neuroprotective effect of ceftriaxone on the penumbra in a rat venous ischemia model. Neuroscience 242:1–10PubMedGoogle Scholar
  139. 139.
    Ouyang YB et al (2007) Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J Neurosci 27:4253–4260PubMedCentralPubMedGoogle Scholar
  140. 140.
    Thone-Reineke C et al (2008) The beta-lactam antibiotic, ceftriaxone, dramatically improves survival, increases glutamate uptake and induces neurotrophins in stroke. J Hypertens 26:2426–2435PubMedGoogle Scholar
  141. 141.
    Verma R et al (2010) Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury. Eur J Pharmacol 638:65–71PubMedGoogle Scholar
  142. 142.
    Amalric M (2015) Targeting metabotropic glutamate receptors (mGluRs) in Parkinson’s disease. Curr Opin Pharmacol 20:29–34PubMedGoogle Scholar
  143. 143.
    Blandini F et al (2000) Functional changes of the basal ganglia circuitry in Parkinson’s disease. Prog Neurobiol 62:63–88PubMedGoogle Scholar
  144. 144.
    Gardoni F, Di Luca M (2015) Targeting glutamatergic synapses in Parkinson’s disease. Curr Opin Pharmacol 20:24–28PubMedGoogle Scholar
  145. 145.
    Chung EK et al (2008) Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6-hydroxydopamine-lesioned rats. J Comp Neurol 511:421–437PubMedGoogle Scholar
  146. 146.
    Holmer HK et al (2005) l-dopa-induced reversal in striatal glutamate following partial depletion of nigrostriatal dopamine with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience 136:333–341PubMedGoogle Scholar
  147. 147.
    Bisht R et al (2014) Ceftriaxone mediated rescue of nigral oxidative damage and motor deficits in MPTP model of Parkinson’s disease in rats. Neurotoxicology 44:71–79PubMedGoogle Scholar
  148. 148.
    Chotibut T et al (2014) Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson’s model. Mol Neurobiol 49:1282–1292PubMedGoogle Scholar
  149. 149.
    Ho SC et al (2014) Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson’s disease rat model. Behav Brain Res 268:177–184PubMedGoogle Scholar
  150. 150.
    Hsu CY et al (2015) Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson’s disease dementia. Neuropharmacology 91:43–56PubMedGoogle Scholar
  151. 151.
    Kelsey JE, Neville C (2014) The effects of the beta-lactam antibiotic, ceftriaxone, on forepaw stepping and L-DOPA-induced dyskinesia in a rodent model of Parkinson’s disease. Psychopharmacology 231:2405–2415PubMedGoogle Scholar
  152. 152.
    Leung TC et al (2012) Ceftriaxone ameliorates motor deficits and protects dopaminergic neurons in 6-hydroxydopamine-lesioned rats. ACS Chem Neurosci 3:22–30PubMedCentralPubMedGoogle Scholar
  153. 153.
    McNamara JO et al (2006) Molecular signaling mechanisms underlying epileptogenesis. Sci STKE 2006:re12PubMedGoogle Scholar
  154. 154.
    Pitkanen A, Lukasiuk K (2011) Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10:173–186PubMedGoogle Scholar
  155. 155.
    Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60:1215–1226PubMedCentralPubMedGoogle Scholar
  156. 156.
    Jabs R et al (2008) Astrocytic function and its alteration in the epileptic brain. Epilepsia 49(Suppl 2):3–12PubMedGoogle Scholar
  157. 157.
    Cavus I et al (2005) Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann Neurol 57:226–235PubMedGoogle Scholar
  158. 158.
    During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610PubMedGoogle Scholar
  159. 159.
    Bjornsen LP et al (2007) Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures. Neurobiol Dis 25:319–330PubMedGoogle Scholar
  160. 160.
    Mathern GW et al (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472PubMedGoogle Scholar
  161. 161.
    Proper EA et al (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43PubMedGoogle Scholar
  162. 162.
    Sarac S et al (2009) Excitatory amino acid transporters EAAT-1 and EAAT-2 in temporal lobe and hippocampus in intractable temporal lobe epilepsy. APMIS 117:291–301PubMedGoogle Scholar
  163. 163.
    Tessler S et al (1999) Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience 88:1083–1091PubMedGoogle Scholar
  164. 164.
    Benarroch EE (2009) Astrocyte-neuron interactions: implications for epilepsy. Neurology 73:1323–1327PubMedGoogle Scholar
  165. 165.
    Binder DK, Steinhauser C (2006) Functional changes in astroglial cells in epilepsy. Glia 54:358–368PubMedGoogle Scholar
  166. 166.
    Tian GF et al (2005) An astrocytic basis of epilepsy. Nat Med 11:973–981PubMedCentralPubMedGoogle Scholar
  167. 167.
    Wetherington J et al (2008) Astrocytes in the epileptic brain. Neuron 58:168–178PubMedCentralPubMedGoogle Scholar
  168. 168.
    Jelenkovic AV et al (2008) Beneficial effects of ceftriaxone against pentylenetetrazole-evoked convulsions. Exp Biol Med (Maywood) 233:1389–1394Google Scholar
  169. 169.
    Zeng LH et al (2010) Modulation of astrocyte glutamate transporters decreases seizures in a mouse model of Tuberous Sclerosis complex. Neurobiol Dis 37:764–771PubMedCentralPubMedGoogle Scholar
  170. 170.
    Goodrich GS et al (2013) Ceftriaxone treatment after traumatic brain injury restores expression of the glutamate transporter, GLT-1, reduces regional gliosis, and reduces post-traumatic seizures in the rat. J Neurotrauma 30:1434–1441PubMedCentralPubMedGoogle Scholar
  171. 171.
    Kong Q et al (2012) Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus. Neurobiol Dis 47:145–154PubMedCentralPubMedGoogle Scholar
  172. 172.
    Kiernan MC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955PubMedGoogle Scholar
  173. 173.
    Rothstein JD (2009) Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 65(Suppl 1):S3–S9PubMedGoogle Scholar
  174. 174.
    Rothstein JD et al (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84PubMedGoogle Scholar
  175. 175.
    Bendotti C et al (2001) Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem 79:737–746PubMedGoogle Scholar
  176. 176.
    Bruijn LI et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338PubMedGoogle Scholar
  177. 177.
    Howland DS et al (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99:1604–1609PubMedCentralPubMedGoogle Scholar
  178. 178.
    Guo H et al (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 12:2519–2532PubMedGoogle Scholar
  179. 179.
    Cudkowicz ME et al (2014) Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:1083–1091PubMedGoogle Scholar
  180. 180.
    Bell KF et al (2007) Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment. J Neurosci 27:10810–10817PubMedGoogle Scholar
  181. 181.
    Jacob CP et al (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11:97–116PubMedGoogle Scholar
  182. 182.
    Kashani A et al (2008) Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiol Aging 29:1619–1630PubMedGoogle Scholar
  183. 183.
    Kirvell SL et al (2006) Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer’s disease. J Neurochem 98:939–950PubMedGoogle Scholar
  184. 184.
    Masliah E et al (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 40:759–766PubMedGoogle Scholar
  185. 185.
    Scott HA et al (2011) Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiol Aging 32:553 e1–553 e11PubMedGoogle Scholar
  186. 186.
    Sokolow S et al (2012) Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer’s disease cortex. Neurobiol Dis 45:381–387PubMedCentralPubMedGoogle Scholar
  187. 187.
    Bordji K et al (2010) Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-β production. J Neurosci 30:15927–15942PubMedGoogle Scholar
  188. 188.
    Kim SH et al (2010) Group II metabotropic glutamate receptor stimulation triggers production and release of Alzheimer’s amyloid(beta)42 from isolated intact nerve terminals. J Neurosci 30:3870–3875PubMedCentralPubMedGoogle Scholar
  189. 189.
    Lesne S et al (2005) NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J Neurosci 25:9367–9377PubMedGoogle Scholar
  190. 190.
    Chin JH et al (2007) Amyloid beta protein modulates glutamate-mediated neurotransmission in the rat basal forebrain: involvement of presynaptic neuronal nicotinic acetylcholine and metabotropic glutamate receptors. J Neurosci 27:9262–9269PubMedGoogle Scholar
  191. 191.
    Kabogo D et al (2010) β-amyloid-related peptides potentiate K+-evoked glutamate release from adult rat hippocampal slices. Neurobiol Aging 31:1164–1172PubMedGoogle Scholar
  192. 192.
    Talantova M et al (2013) Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA 110:E2518–E2527PubMedCentralPubMedGoogle Scholar
  193. 193.
    Li S et al (2009) Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62:788–801PubMedCentralPubMedGoogle Scholar
  194. 194.
    Li S et al (2011) Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 31:6627–6638PubMedCentralPubMedGoogle Scholar
  195. 195.
    Shankar GM et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842PubMedCentralPubMedGoogle Scholar
  196. 196.
    Wang Q et al (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 24:3370–3378PubMedGoogle Scholar
  197. 197.
    Bechtholt-Gompf AJ et al (2010) Blockade of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. Neuropsychopharmacology 35:2049–2059PubMedCentralPubMedGoogle Scholar
  198. 198.
    Heo S et al (2012) Hippocampal glutamate transporter 1 (GLT-1) complex levels are paralleling memory training in the Multiple T-maze in C57BL/6J mice. Brain Struct Funct 217:363–378PubMedGoogle Scholar
  199. 199.
    Li S et al (1997) Glutamate transporter alterations in Alzheimer disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol 56:901–911PubMedGoogle Scholar
  200. 200.
    Takahashi K et al (2015) Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease. J Exp Med 212:319–332PubMedGoogle Scholar
  201. 201.
    Alonso J et al (2004) Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand 109(Suppl 420):21–27Google Scholar
  202. 202.
    Kessler RC et al (2005) Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:593–602PubMedGoogle Scholar
  203. 203.
    Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3:e442PubMedCentralPubMedGoogle Scholar
  204. 204.
    Hamilton JP et al (2012) Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data. Am J Psychiatry 169:693–703PubMedGoogle Scholar
  205. 205.
    Siegle GJ et al (2007) Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry 61:198–209PubMedGoogle Scholar
  206. 206.
    Rajkowska G, Stockmeier CA (2013) Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 14:1225–1236PubMedCentralPubMedGoogle Scholar
  207. 207.
    Sanacora G, Banasr M (2013) From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry 73:1172–1179PubMedCentralPubMedGoogle Scholar
  208. 208.
    Bowley MP et al (2002) Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 52:404–412PubMedGoogle Scholar
  209. 209.
    Cotter D et al (2002) Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex 12:386–394PubMedGoogle Scholar
  210. 210.
    Cotter D et al (2001) Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry 58:545–553PubMedGoogle Scholar
  211. 211.
    Gittins RA, Harrison PJ (2011) A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder. J Affect Disord 133:328–332PubMedGoogle Scholar
  212. 212.
    Ongur D et al (1998) Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 95:13290–13295PubMedCentralPubMedGoogle Scholar
  213. 213.
    Rajkowska G et al (1999) Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45:1085–1098PubMedGoogle Scholar
  214. 214.
    Altshuler LL et al (2010) Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord 12:541–549PubMedGoogle Scholar
  215. 215.
    Choudary PV et al (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 102:15653–15658PubMedCentralPubMedGoogle Scholar
  216. 216.
    Miguel-Hidalgo JJ et al (2010) Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J Affect Disord 127:230–240PubMedCentralPubMedGoogle Scholar
  217. 217.
    Si X et al (2004) Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression. Neuropsychopharmacology 29:2088–2096PubMedCentralPubMedGoogle Scholar
  218. 218.
    Banasr M, Duman RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 64:863–870PubMedCentralPubMedGoogle Scholar
  219. 219.
    Czeh B et al (2006) Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 31:1616–1626PubMedGoogle Scholar
  220. 220.
    Banasr M et al (2010) Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15:501–511PubMedCentralPubMedGoogle Scholar
  221. 221.
    Sanacora G et al (2007) Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 61:822–825PubMedGoogle Scholar
  222. 222.
    Takahashi K et al (2011) Riluzole rapidly attenuates hyperemotional responses in olfactory bulbectomized rats, an animal model of depression. Behav Brain Res 216:46–52PubMedGoogle Scholar
  223. 223.
    Zarate CA Jr et al (2004) An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 161:171–174PubMedGoogle Scholar
  224. 224.
    Gilad GM et al (1990) Region-selective stress-induced increase of glutamate uptake and release in rat forebrain. Brain Res 525:335–338PubMedGoogle Scholar
  225. 225.
    Musazzi L et al (2010) Acute stress increases depolarization-evoked glutamate release in the rat prefrontal/frontal cortex: the dampening action of antidepressants. PLoS One 5:e8566PubMedCentralPubMedGoogle Scholar
  226. 226.
    Satoh E, Shimeki S (2010) Acute restraint stress enhances calcium mobilization and glutamate exocytosis in cerebrocortical synaptosomes from mice. Neurochem Res 35:693–701PubMedGoogle Scholar
  227. 227.
    Autry AE et al (2006) Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus. Neuroendocrinology 83:371–379PubMedGoogle Scholar
  228. 228.
    Fontella FU et al (2004) Repeated restraint stress alters hippocampal glutamate uptake and release in the rat. Neurochem Res 29:1703–1709PubMedGoogle Scholar
  229. 229.
    Reagan LP et al (2004) Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc Natl Acad Sci USA 101:2179–2184PubMedGoogle Scholar
  230. 230.
    Zschocke J et al (2005) Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. J Biol Chem 280:34924–34932PubMedGoogle Scholar
  231. 231.
    Parihar VK et al (2011) Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory. Mol Psychiatry 16:171–183PubMedCentralPubMedGoogle Scholar
  232. 232.
    Suo L et al (2013) Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology 38:1387–1400PubMedCentralPubMedGoogle Scholar
  233. 233.
    Chen JX et al (2014) Glutamate transporter 1-mediated antidepressant-like effect in a rat model of chronic unpredictable stress. J Huazhong Univ Sci Technolog Med Sci 34:838–844PubMedGoogle Scholar
  234. 234.
    Zink M et al (2010) Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology 58:465–473PubMedGoogle Scholar
  235. 235.
    John CS et al (2012) Blockade of astrocytic glutamate uptake in the prefrontal cortex induces anhedonia. Neuropsychopharmacology 37:2467–2475PubMedCentralPubMedGoogle Scholar
  236. 236.
    Lee Y et al (2007) Glia mechanisms in mood regulation: a novel model of mood disorders. Psychopharmacology 191:55–65PubMedGoogle Scholar
  237. 237.
    Cui W et al (2014) Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci 34:16273–16285PubMedGoogle Scholar
  238. 238.
    Mineur YS et al (2007) Antidepressant-like effects of ceftriaxone in male C57BL/6J mice. Biol Psychiatry 61:250–252PubMedGoogle Scholar
  239. 239.
    Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159:1642–1652PubMedCentralPubMedGoogle Scholar
  240. 240.
    Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572PubMedGoogle Scholar
  241. 241.
    Gass JT et al (2011) Alcohol-seeking behavior is associated with increased glutamate transmission in basolateral amygdala and nucleus accumbens as measured by glutamate-oxidase-coated biosensors. Addict Biol 16:215–228PubMedCentralPubMedGoogle Scholar
  242. 242.
    Gipson CD et al (2013) Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci USA 110:9124–9129PubMedCentralPubMedGoogle Scholar
  243. 243.
    LaLumiere RT, Kalivas PW (2008) Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci 28:3170–3177PubMedGoogle Scholar
  244. 244.
    McFarland K et al (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537PubMedGoogle Scholar
  245. 245.
    Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16:974–986PubMedCentralPubMedGoogle Scholar
  246. 246.
    Fischer-Smith KD et al (2012) Differential effects of cocaine access and withdrawal on glutamate type 1 transporter expression in rat nucleus accumbens core and shell. Neuroscience 210:333–339PubMedCentralPubMedGoogle Scholar
  247. 247.
    Knackstedt LA et al (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67:81–84PubMedCentralPubMedGoogle Scholar
  248. 248.
    Shen HW et al (2014) Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse. J Neurosci 34:5649–5657PubMedCentralPubMedGoogle Scholar
  249. 249.
    Abulseoud OA et al (2014) Attenuation of ethanol withdrawal by ceftriaxone-induced upregulation of glutamate transporter EAAT2. Neuropsychopharmacology 39:1674–1684PubMedGoogle Scholar
  250. 250.
    Alhaddad H et al (2014) Effects of ceftriaxone on ethanol intake: a possible role for xCT and GLT-1 isoforms modulation of glutamate levels in P rats. Psychopharmacology 231:4049–4057PubMedCentralPubMedGoogle Scholar
  251. 251.
    Qrunfleh AM et al (2013) Ceftriaxone, a beta-lactam antibiotic, attenuates relapse-like ethanol-drinking behavior in alcohol-preferring rats. J Psychopharmacol 27:541–549PubMedCentralPubMedGoogle Scholar
  252. 252.
    Sari Y et al (2011) Ceftriaxone, a beta-lactam antibiotic, reduces ethanol consumption in alcohol-preferring rats. Alcohol Alcohol 46:239–246PubMedCentralPubMedGoogle Scholar
  253. 253.
    Rawls SM et al (2010) beta-Lactam antibiotic inhibits development of morphine physical dependence in rats. Behav Pharmacol 21:161–164PubMedCentralPubMedGoogle Scholar
  254. 254.
    Sari Y et al (2009) Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. J Neurosci 29:9239–9243PubMedCentralPubMedGoogle Scholar
  255. 255.
    Sondheimer I, Knackstedt LA (2011) Ceftriaxone prevents the induction of cocaine sensitization and produces enduring attenuation of cue- and cocaine-primed reinstatement of cocaine-seeking. Behav Brain Res 225:252–258PubMedCentralPubMedGoogle Scholar
  256. 256.
    Trantham-Davidson H et al (2012) Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. J Neurosci 32:12406–12410PubMedCentralPubMedGoogle Scholar
  257. 257.
    Reissner KJ et al (2014) Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. Neuropsychopharmacology 39:499–506PubMedCentralPubMedGoogle Scholar
  258. 258.
    Abulseoud OA et al (2012) Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm. Brain Res 1456:14–21PubMedCentralPubMedGoogle Scholar
  259. 259.
    Alajaji M et al (2013) Effects of the beta-lactam antibiotic ceftriaxone on nicotine withdrawal and nicotine-induced reinstatement of preference in mice. Psychopharmacology 228:419–426PubMedGoogle Scholar
  260. 260.
    Lauriat TL, McInnes LA (2007) EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders. Mol Psychiatry 12:1065–1078PubMedGoogle Scholar
  261. 261.
    Nakagawa T, Kaneko S (2013) SLC1 glutamate transporters and diseases: psychiatric diseases and pathological pain. Curr Mol Pharmacol 6:66–73PubMedGoogle Scholar
  262. 262.
    Melone M et al (2009) GLT-1 up-regulation enhances the effect of PCP on prepulse inhibition of the startle reflex in adult rats. Schizophr Res 109:196–197PubMedGoogle Scholar
  263. 263.
    Lin CL et al (2012) Glutamate transporter EAAT2: a new target for the treatment of neurodegenerative diseases. Future Med Chem 4:1689–1700PubMedCentralPubMedGoogle Scholar
  264. 264.
    Yi JH, Hazell AS (2006) Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int 48:394–403PubMedGoogle Scholar
  265. 265.
    Cui C et al (2014) Neuroprotective effect of ceftriaxone in a rat model of traumatic brain injury. Neurol Sci 35:695–700PubMedGoogle Scholar
  266. 266.
    Maragakis NJ, Rothstein JD (2004) Glutamate transporters: animal models to neurologic disease. Neurobiol Dis 15:461–473PubMedGoogle Scholar
  267. 267.
    Sheldon AL, Robinson MB (2007) The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int 51:333–355PubMedCentralPubMedGoogle Scholar
  268. 268.
    Miller BR et al (2008) Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience 153:329–337PubMedCentralPubMedGoogle Scholar
  269. 269.
    Gegelashvili G, Bjerrum OJ (2014) High-affinity glutamate transporters in chronic pain: an emerging therapeutic target. J Neurochem 131:712–730PubMedGoogle Scholar
  270. 270.
    Hu Y et al (2010) An anti-nociceptive role for ceftriaxone in chronic neuropathic pain in rats. Pain 148:284–301PubMedGoogle Scholar
  271. 271.
    Ramos KM et al (2010) Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders. Neuroscience 169:1888–1900PubMedCentralPubMedGoogle Scholar
  272. 272.
    Stepanovic-Petrovic RM et al (2014) Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents. Anesthesiology 120:737–750PubMedGoogle Scholar
  273. 273.
    Robert SM, Sontheimer H (2014) Glutamate transporters in the biology of malignant gliomas. Cell Mol Life Sci 71:1839–1854PubMedCentralPubMedGoogle Scholar
  274. 274.
    Melzer N et al (2008) A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis. PLoS One 3:e3149PubMedCentralPubMedGoogle Scholar
  275. 275.
    Autism Genome Project C et al (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328Google Scholar
  276. 276.
    Purcell AE et al (2001) Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57:1618–1628PubMedGoogle Scholar

Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Kou Takahashi
    • 1
  • Joshua B. Foster
    • 1
  • Chien-Liang Glenn Lin
    • 1
    Email author
  1. 1.Department of NeuroscienceThe Ohio State UniversityColumbusUSA

Personalised recommendations