Advertisement

Are glutamate transporters neuroprotective or neurodegenerative during cerebral ischemia?

  • Li-Nan Zhang
  • Liang Hao
  • Yu-Song Guo
  • Hai-Yan Wang
  • Lin-lin Li
  • Li-Zhe Liu
  • Wen-Bin LiEmail author
Review
  • 72 Downloads

Abstract

The accumulation of glutamate (Glu) in the synaptic cleft during cerebral ischemia triggers the death of neurons, causing mental or physical handicap. However, the mechanisms of the alteration in Glu homeostasis and the imbalance between the release and clearance of Glu in ischemia are not yet completely understood. Additionally, the role of Glu transporters in regulating Glu concentration in the synaptic cleft is controversial. This review aims to provide readers with an in-depth understanding of Glu transporters in the early or later stages of ischemic events, or in mild or severe cerebral ischemia via alteration of Glu transporter expression, reversal of Glu transporters function, and trafficking between membrane and cytoplasm, to further clarify whether the Glu transporters are neuroprotective or neurodegenerative during cerebral ischemia. We provide the insights for deeper understanding of the mechanism of Glu transporters regulation after different periods and severities of cerebral ischemia.

Keywords

Glutamate transporter Cerebral ischemia Reversal Trafficking Expression 

Notes

Acknowledgements

These authors acknowledge the support received for this study from the Natural Science Foundation of China (NSFC81402886), the Natural Science Foundation of Hebei Province (H2016208071), and Hebei Province hundred excellent innovative talents support scheme (III) (SLRC2017044).

Author contribution

Zhang LN designed the research concept; Hao L and Guo YS analyzed data and interpreted; Wang HY and Li LL collected the data; Liu L made the table; Zhang LN and Li WB checked the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Herman MA, Jahr CE (2007) Extracellular glutamate concentration in hippocampal slice. J Neurosci 27:9736–9741CrossRefGoogle Scholar
  2. 2.
    Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC, Stebbins JL, Pellecchia M, Sarkar D, Fisher PB (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226:2484–2493CrossRefGoogle Scholar
  3. 3.
    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 13:713–725CrossRefGoogle Scholar
  4. 4.
    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 15:1835–1853CrossRefGoogle Scholar
  5. 5.
    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 15:711–720CrossRefGoogle Scholar
  6. 6.
    Amara SG, Fontana AC (2002) Excitatory amino acid transporters: keeping up with glutamate. Neurochem Int 41:313–318CrossRefGoogle Scholar
  7. 7.
    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 203:1–20CrossRefGoogle Scholar
  8. 8.
    Vandenberg RJ (1998) Molecular pharmacology and physiology of glutamate transporters in the central nervous system. Clin Exp Pharmacol Physiol 25:393–400CrossRefGoogle Scholar
  9. 9.
    Kanai Y, Hediger MA (2003) The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. Eur J Pharmacol 479:237–247CrossRefGoogle Scholar
  10. 10.
    Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702CrossRefGoogle Scholar
  11. 11.
    Robinson MB (1998) The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype. Neurochem Int 33:479–491CrossRefGoogle Scholar
  12. 12.
    Maragakis NJ, Dietrich J, Wong V, Xue H, Mayer-Proschel M, Rao MS, Rothstein JD (2004) Glutamate transporter expression and function in human glial progenitors. Glia 45:133–143CrossRefGoogle Scholar
  13. 13.
    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 18:8751–8757CrossRefGoogle Scholar
  14. 14.
    Suchak SK, Baloyianni NV, Perkinton MS, Williams RJ, Meldrum BS, Rattray M (2003) The ‘glial’ glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. J Neurochem 84:522–532CrossRefGoogle Scholar
  15. 15.
    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 18:9620–9628CrossRefGoogle Scholar
  16. 16.
    Owe SG, Marcaggi P, Attwell D (2006) The ionic stoichiometry of the GLAST glutamate transporter in salamander retinal glia. J Physiol 577:591–599CrossRefGoogle Scholar
  17. 17.
    Zerangue N, Kavanaugh MP (1996) Flux coupling in a neuronal glutamate transporter. Nature 383:634–637CrossRefGoogle Scholar
  18. 18.
    Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403:316–321CrossRefGoogle Scholar
  19. 19.
    Torp R, Lekieffre D, Levy LM, Haug FM, Danbolt NC, Meldrum BS, Ottersen OP (1995) Reduced postischemic expression of a glial glutamate transporter, GLT1, in the rat hippocampus. Exp Brain Res 103:51–58CrossRefGoogle Scholar
  20. 20.
    Harvey BK, Airavaara M, Hinzman J, Wires EM, Chiocco MJ, Howard DB, Shen H, Gerhardt G, Hoffer BJ, Wang Y (2011) Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke. PLoS One 6:e22135.  https://doi.org/10.1371/journal.pone.0022135 CrossRefGoogle Scholar
  21. 21.
    Yatomi Y, Tanaka R, Shimura H, Miyamoto N, Yamashiro K, Takanashi M, Urabe T, Hattori N (2013) Chronic brain ischemia induces the expression of glial glutamate transporter EAAT2 in subcortical white matter. Neuroscience 244:113–121CrossRefGoogle Scholar
  22. 22.
    Inage YW, Itoh M, Wada K, Takashima S (1998) Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlation in development and neonatal hypoxic-ischemic damage. J Neuropathol Exp Neurol 57:554–562CrossRefGoogle Scholar
  23. 23.
    Szatkowski M, Attwell D (1994) Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci 17:359–365CrossRefGoogle Scholar
  24. 24.
    Murphy-Royal C, Dupuis JP, Varela JA, Panatier A, Pinson B, Baufreton J, Groc L, Oliet SH (2015) Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission. Nat Neurosci 18:219–226CrossRefGoogle Scholar
  25. 25.
    Arranz AM, Gottlieb M, Perez-Cerda F, Matute C (2010) Increased expression of glutamate transporters in subcortical white matter after transient focal cerebral ischemia. Neurobiol Dis 37:156–165CrossRefGoogle Scholar
  26. 26.
    Russo R, Cavaliere F, Varano GP, Milanese M, Adornetto A, Nucci C, Bonanno G, Morrone LA, Corasaniti MT, Bagetta G (2013) Impairment of neuronal glutamate uptake and modulation of the glutamate transporter GLT-1 induced by retinal ischemia. PLoS One 8:e69250.  https://doi.org/10.1371/journal.pone.0069250 CrossRefGoogle Scholar
  27. 27.
    Liu YX, Zhang M, Liu LZ, Cui X, Hu YY, Li WB (2012) The role of glutamate transporter-1a in the induction of brain ischemic tolerance in rats. Glia 60:112–124CrossRefGoogle Scholar
  28. 28.
    Girbovan C, Plamondon H (2015) Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats. Brain Res 1608:203–214CrossRefGoogle Scholar
  29. 29.
    Kim DS, Kwak SE, Kim JE, Jung JY, Won MH, Choi SY, Kwon OS, Kang TC (2006) Transient ischaemia affects plasma membrane glutamate transporter, not vesicular glutamate transporter, expressions in the gerbil hippocampus. Anat Histol Embryol 35:265–270CrossRefGoogle Scholar
  30. 30.
    Fang Q, Hu WW, Wang XF, Yang Y, Lou GD, Jin MM, Yan HJ, Zeng WZ, Shen Y, Zhang SH, Xu TL, Chen Z (2014) Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury. Neuropharmacology 77:156–166CrossRefGoogle Scholar
  31. 31.
    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 42:335–348CrossRefGoogle Scholar
  32. 32.
    Cui X, Li L, Hu YY, Ren S, Zhang M, Li WB (2015) Sulbactam plays neuronal protective effect against brain ischemia via upregulating GLT1 in rats. Mol Neurobiol 51:1322–1333CrossRefGoogle Scholar
  33. 33.
    Jimenez E, Nunez E, Ibanez I, Draffin JE, Zafra F, Gimenez C (2014) Differential regulation of the glutamate transporters GLT-1 and GLAST by GSK3beta. Neurochem Int 79:33–43CrossRefGoogle Scholar
  34. 34.
    Ji YF, Zhou L, Xie YJ, Xu SM, Zhu J, Teng P, Shao CY, Wang Y, Luo JH, Shen Y (2013) Upregulation of glutamate transporter GLT-1 by mTOR-Akt-NF-small ka, CyrillicB cascade in astrocytic oxygen-glucose deprivation. Glia 61:1959–1975CrossRefGoogle Scholar
  35. 35.
    Sun P, Zhang S, Li Y, Wang L (2014) Harmine mediated neuroprotection via evaluation of glutamate transporter 1 in a rat model of global cerebral ischemia. Neurosci Lett 583:32–36CrossRefGoogle Scholar
  36. 36.
    Chu K, Lee ST, Sinn DI, Ko SY, Kim EH, Kim JM, Kim SJ, Park DK, Jung KH, Song EC, Lee SK, Kim M, Roh JK (2007) Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke 38:177–182CrossRefGoogle Scholar
  37. 37.
    Hu YY, Xu J, Zhang M, Wang D, Li L, Li WB (2015) Ceftriaxone modulates uptake activity of glial glutamate transporter-1 against global brain ischemia in rats. J Neurochem 132:194–205CrossRefGoogle Scholar
  38. 38.
    Verma R, Mishra V, Sasmal D, Raghubir R (2010) Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury. Eur J Pharmacol 638:65–71CrossRefGoogle Scholar
  39. 39.
    Jagadapillai R, Mellen NM, Sachleben LR Jr, Gozal E (2014) Ceftriaxone preserves glutamate transporters and prevents intermittent hypoxia-induced vulnerability to brain excitotoxic injury. PLoS One 9:e100230.  https://doi.org/10.1371/journal.pone.0100230 CrossRefGoogle Scholar
  40. 40.
    Yang ZB, Zhang Z, Li TB, Lou Z, Li SY, Yang H, Yang J, Luo XJ, Peng J (2014) Up-regulation of brain-enriched miR-107 promotes excitatory neurotoxicity through down-regulation of glutamate transporter-1 expression following ischaemic stroke. Clin Sci 127:679–689CrossRefGoogle Scholar
  41. 41.
    Nishizawa Y (2001) Glutamate release and neuronal damage in ischemia. Life Sci 69:369–381CrossRefGoogle Scholar
  42. 42.
    Phillis JW, Ren J, O’Regan MH (2000) Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-threo-beta-benzyloxyaspartate. Brain Res 880:224CrossRefGoogle Scholar
  43. 43.
    Wang D, Zhao Y, Zhang Y, Zhang T, Shang X, Wang J, Liu Y, Kong Q, Sun B, Mu L, Liu X, Wang G, Li H (2013) Hypothermia protects against oxygen-glucose deprivation-induced neuronal injury by down-regulating the reverse transport of glutamate by astrocytes as mediated by neurons. Neuroscience 237:130–138CrossRefGoogle Scholar
  44. 44.
    Kosugi T, Kawahara K (2006) Reversed actrocytic GLT-1 during ischemia is crucial to excitotoxic death of neurons, but contributes to the survival of astrocytes themselves. Neurochem Res 31:933–943CrossRefGoogle Scholar
  45. 45.
    Gebhardt C, Korner R, Heinemann U (2002) Delayed anoxic depolarizations in hippocampal neurons of mice lacking the excitatory amino acid carrier 1. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 22:569–575CrossRefGoogle Scholar
  46. 46.
    Jabaudon D, Scanziani M, Gahwiler BH, Gerber U (2000) Acute decrease in net glutamate uptake during energy deprivation. Proc Natl Acad Sci U S A 97:5610–5615CrossRefGoogle Scholar
  47. 47.
    Hamann M, Rossi DJ, Marie H, Attwell D (2002) Knocking out the glial glutamate transporter GLT-1 reduces glutamate uptake but does not affect hippocampal glutamate dynamics in early simulated ischaemia. Eur J Neurosci 15:308–314CrossRefGoogle Scholar
  48. 48.
    Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348:443–446CrossRefGoogle Scholar
  49. 49.
    Mennerick S, Shen W, Xu W, Benz A, Tanaka K, Shimamoto K, Isenberg KE, Krause JE, Zorumski CF (1999) Substrate turnover by transporters curtails synaptic glutamate transients. J Neurosci 19:9242–9251CrossRefGoogle Scholar
  50. 50.
    Takahashi M, Billups B, Rossi D, Sarantis M, Hamann M, Attwell D (1997) The role of glutamate transporters in glutamate homeostasis in the brain. J Exp Biol 200:401–409Google Scholar
  51. 51.
    Pilc A, Chaki S, Nowak G, Witkin JM (2008) Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol 75:997–1006CrossRefGoogle Scholar
  52. 52.
    Li S, Mealing GA, Morley P, Stys PK (1999) Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport. J Neurosci 19:RC16CrossRefGoogle Scholar
  53. 53.
    Kauppinen RA, McMahon HT, Nicholls DG (1988) Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca2+ concentration in isolated nerve terminals following metabolic inhibition: possible relevance to hypoglycaemia and anoxia. Neuroscience 27:175–182CrossRefGoogle Scholar
  54. 54.
    Attwell D, Barbour B, Szatkowski M (1993) Nonvesicular release of neurotransmitter. Neuron 11:401–407CrossRefGoogle Scholar
  55. 55.
    Billups B, Attwell D (1996) Modulation of non-vesicular glutamate release by pH. Nature 379:171–174CrossRefGoogle Scholar
  56. 56.
    Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP (1995) Kinetics of a human glutamate transporter. Neuron 14:1019–1027CrossRefGoogle Scholar
  57. 57.
    Duan S, Anderson CM, Stein BA, Swanson RA (1999) Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J Neurosci 19:10193–10200CrossRefGoogle Scholar
  58. 58.
    Tran-Ba KH, Higgins DA, Ito T (2015) Fluorescence recovery after photobleaching and single-molecule tracking measurements of anisotropic diffusion within identical regions of a cylinder-forming diblock copolymer film. Anal Chem 87:5802–5809CrossRefGoogle Scholar
  59. 59.
    Al Awabdh S, Gupta-Agarwal S, Sheehan DF, Muir J, Norkett R, Twelvetrees AE, Griffin LD, Kittler JT (2016) Neuronal activity mediated regulation of glutamate transporter GLT-1 surface diffusion in rat astrocytes in dissociated and slice cultures. Glia 64:1252–1264CrossRefGoogle Scholar
  60. 60.
    Martinez-Villarreal J, Garcia Tardon N, Ibanez I, Gimenez C, Zafra F (2012) Cell surface turnover of the glutamate transporter GLT-1 is mediated by ubiquitination/deubiquitination. Glia 60:1356–1365CrossRefGoogle Scholar
  61. 61.
    Li D, Herault K, Zylbersztejn K, Lauterbach MA, Guillon M, Oheim M, Ropert N (2015) Astrocyte VAMP3 vesicles undergo Ca2+ -independent cycling and modulate glutamate transporter trafficking. J Physiol 593:2807–2832CrossRefGoogle Scholar
  62. 62.
    Yan X, Yadav R, Gao M, Weng HR (2014) Interleukin-1 beta enhances endocytosis of glial glutamate transporters in the spinal dorsal horn through activating protein kinase C. Glia 62:1093–1109CrossRefGoogle Scholar
  63. 63.
    Benediktsson AM, Marrs GS, Tu JC, Worley PF, Rothstein JD, Bergles DE, Dailey ME (2012) Neuronal activity regulates glutamate transporter dynamics in developing astrocytes. Glia 60:175–188CrossRefGoogle Scholar
  64. 64.
    Sheean RK, Lau CL, Shin YS, O’Shea RD, Beart PM (2013) Links between L-glutamate transporters, Na+/K+-ATPase and cytoskeleton in astrocytes: evidence following inhibition with rottlerin. Neuroscience 254:335–346CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PathophysiologyHebei Medical UniversityShijiazhuangChina
  2. 2.Department of NeurosurgeryThird Hospital of ShijiazhuangBeijingChina
  3. 3.Department of TraumatologyThird Hospital of ShijiazhuangBeijingChina
  4. 4.Pharmaceutical Preparation SectionThird Hospital of ShijiazhuangBeijingChina
  5. 5.Clinical Medicine, College of Basic MedicineHebei Medical UniversityBeijingChina

Personalised recommendations