Skip to main content
Log in

The expression of astroglial glutamate transporters in patients with focal cortical dysplasia: an immunohistochemical study

  • Clinico Pathological Studies
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Abstract

Purpose

An abnormal increase in the extracellular glutamate is thought to play a crucial role in the initiation, spread, and maintenance of seizure activity.In normal conditions, the majority of this excess glutamate is cleared via glial glutamate transporters (EAAT-1 and EAAT-2). We aimed to examine the immunohistochemical expression of these transporters in the dysplastic tissues of patients with focal cortical dysplasia (FCD).

Methods

The parafin-embedded dysplastic tissues of 33 patients who were operated on due to medically intractable epilepsy and histopathologically diagnosed with FCD between 2001 and 2006 were stained immunohistochemically with appropriate antibodies, and the distribution and intensity of immunoreactivity (IR) of EAAT-1 and EAAT-2 were examined.The findings were compared with the histologically normal tissues of five patients who underwent temporal lobectomy for epilepsy surgery and 10 fresh postmortem cases.

Results

In the majority of the patients, the EAAT-1 and EAAT-2 IR were decreased, their astrocytic expression were lower, and the pattern of distribution were more diffused when compared to the control groups.Analyzing these findings according to the types of FCD revealed that as the severity of the dysplasia increased, the IR and astrocytic expression of both transporters are decreased and their distribution tend to be more “diffused.”

Conclusion

The results of this study suggest a relationship between the decreased glutamate transporter expressions in dysplastic tissues which,in turn, may cause increased extracellular concentrations of glutamate and FCD pathophysiology.Further studies with larger patient populations,investigating the expression of glutamate transporters at mRNA and protein levels, are required to clarify their roles in the pathophysiology of FCD.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Akbar MT, Rattray M, Williams RJ, Chong NW, Meldrum BS (1998) Reduction of GABA and glutamate transporter messenger RNAs in the severe-seizure genetically epilepsy-prone rat. Neuroscience 85:1235–1251

    Article  PubMed  CAS  Google Scholar 

  2. Akbar MT, Torp R, Danbolt NC, Levy LM, Meldrum BS, Ottersen OP (1997) Expression of glial glutamate transporters GLT-1 and GLAST is unchanged in the hippocampus in fully kindled rats. Neuroscience 78:351–359

    Article  PubMed  CAS  Google 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

    Article  PubMed  CAS  Google Scholar 

  4. Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14:5559–5569

    PubMed  CAS  Google Scholar 

  5. Binder DK, Steinhäuser C (2006) Functional changes in astroglial cells in epilepsy. Glia 54(5):358–368

    Article  PubMed  Google Scholar 

  6. Bjornsen LP, Eid T, Holmseth S, Danbolt NC, Spencer DD, de Lanerolle NC (2007) Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures. Neurobiol Dis 25:319–330

    Article  PubMed  CAS  Google Scholar 

  7. Boonyapisit K, Najm I, Klem G, Ying Z, Burrier C, LaPresto E, Nair D, Bingaman W, Prayson R, Lüders H (2003) Epileptogenicity of focal malformations due to abnormal cortical development. Direct electrocorticographic-histopathologic correlations. Epilepsia 44:69–76

    Article  PubMed  Google Scholar 

  8. Bowie D (2008) Ionotropic glutamate receptors & CNS disorders. CNS Neurol Disord Drug Targets 7(2):129–143

    Article  PubMed  CAS  Google Scholar 

  9. Crino PB, Jin H, Shumate MD, Robinson MB, Coulter DA, Brooks-Kayal AR (2002) Increased expression of the neuronal glutamate transporter (EAAT3/EAAC1) in hippocampal and neocortical epilepsy. Epilepsia 43(3):211–218

    Article  PubMed  CAS  Google Scholar 

  10. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. Ingram EM, Wiseman JW, Tessler S, Emson PC (2001) Reduction of glial glutamate transporters in the parietal cortex and hippocampus of the EL mouse. J Neurochem 79:564–575

    Article  PubMed  CAS  Google Scholar 

  13. Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471

    Article  PubMed  CAS  Google Scholar 

  14. Kawakami H, Tanaka K, Nakayama T, Inoue K, Nakamura S (1994) Cloning and expression of a human glutamate transporter. Biochem Biophys Res Commun 199:171–176

    Article  PubMed  CAS  Google Scholar 

  15. 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(5):759–766

    Article  PubMed  CAS  Google Scholar 

  16. Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC, Nelson N, Leite JP, Chimelli L, Born DE, Sakamoto AC, Assirati JA, Fried I, Peacock WJ, Ojemann GA, Adelson PD (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472

    PubMed  CAS  Google Scholar 

  17. Meldrum BS (1993) Amino acids as dietary excitotoxins - a contribution to understanding neurodegenerative disorders. Brain Res Rev 18:293–314

    Article  PubMed  CAS  Google Scholar 

  18. Meldrum BS (1994) The role of glutamate in epilepsy and other CNS disorders. Neurology 44:14–23

    Google Scholar 

  19. Nonaka M, Kohmura E, Yamashita T, Shimada S, Tanaka K, Yoshimine T, Tohyama M, Hayakawa T (1998) Increased transcription of glutamate-aspartate transporter (GLAST/GluT-1) mRNA following kainic acid-induced limbic seizure. Brain Res Mol Brain Res 55:54–60

    Article  PubMed  CAS  Google Scholar 

  20. O’Shea RD (2002) Roles and regulation of glutamate transporters in the central nervous system. Clin Exp Pharmacol Physiol 29:1018–1023

    Article  PubMed  Google Scholar 

  21. Olney JW (1990) Excitotoxic amino acids and neuropsychiatric disorders. Annu Rev Pharmacol Toxicol 30:47–71

    Article  PubMed  CAS  Google Scholar 

  22. Palmini A, Najm I, Avanzini G, Babb T, Guerrini G, Foldvary-Scheaefer N, Jackson G, Lüders HO, Prayson R, Spreafico R, Vinters HV (2004) Terminology and classification of the cortical dysplasias. Neurology 62(Suppl):S2–S8

    PubMed  CAS  Google Scholar 

  23. 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

    Article  PubMed  CAS  Google Scholar 

  24. Rakhade SN, Loeb JA (2008) Focal reduction of neuronal glutamate transporters in human neocortical epilepsy. Epilepsia 49(2):226–236

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. 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(1):73–84

    Article  PubMed  CAS  Google Scholar 

  27. Samuelsson C, Kumlien E, Flink R, Lindholm D, Ronne-Engstrom E (2000) Decreased cortical levels of astrocytic glutamate transport protein GLT-1 in a rat model of posttraumatic epilepsy. Neurosci Lett 289:185–188

    Article  PubMed  CAS  Google Scholar 

  28. Shashidharan P, Michaelidis TM, Robakis NK, Kresovali A, Papamatheakis J, Plaitakis A (1994) Novel human glutamate dehydrogenase expressed in neural and testicular tissues and encoded by an X-linked intronless gene. J Biol Chem 269:16971–16976

    PubMed  CAS  Google Scholar 

  29. 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 tansporter GLT-1. Science 276:1699–1702

    Article  PubMed  CAS  Google Scholar 

  30. Tessler S, Danbolt NC, Faull RL, Storm-Mathisen J, Emson PC (1999) Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience 88:1083–1091

    Article  PubMed  CAS  Google Scholar 

  31. Ueda Y, Doi T, Tokumaru J, Yokoyama H, Nakajima A, Mitsuyama Y, Ohya-Nishiguchi H, Kamada H, Willmore LJ (2001) Collapse of extracellular glutamate regulation during epileptogenesis: downregulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid. J Neurochem 76:892–900

    Article  PubMed  CAS  Google Scholar 

  32. Ure J, Baudry M, Perassolo M (2006) Metabotropic glutamate receptors and epilepsy. J Neurol Sci 247(1):1–9

    Article  PubMed  CAS  Google Scholar 

  33. Wang VY, Chang EF, Barbaro NM (2006) Focal cortical dysplasia: a review of pathological features, genetics, and surgical outcome. Neurosurg Focus 20(1):E7

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by Istanbul University Scientific Research Foundation (İ.Ü. Bilimsel Araştırma Projeleri Birimi/Project No: 961-2007). The authors would like to thank Mehmet Sar, M.D. from the Cerrahpasa Medical Faculty, Department of Pathology for his helping in evaluations of the slides, Sevan Kıran and Meliha Çilek for their technical support in staining processes, Keramettin Kurt, M.D.,the President of the Council of Forensic Medicine, Ministry of Justice, and Professor Murat Hanci, M.D. Department of Neurosurgery, Cerrahpasa Medical Faculty for their constant support.

Conflicts of interest

The authors disclose no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mustafa Onur Ulu.

Additional information

Comments

The authors performed immunohistology stainings on parafin-embedded dysplastic tissues of 33 patients who were operated on for medically intractable epilepsy and were histopathologically diagnosed with focal cortical displasia. The study demonstrates that the astroglial glutamate transporters are significantly downregulated in cortical dysplastic tissue compared with controls. A relationship between the decreased glutamate transporter expressions in dysplastic tissues with increased extracellular concentrations of glutamate and focal cortical displasia pathophysiology is suggested. The study is well designed and has been accurately performed. The manuscript is also well written. Thus, I think that this research study is a valuable contribution for the readership of Acta Neurochir.

Prof. Dr. Joachim Oertel

Mainz, Germany

The authors convincingly show that expression levels of glutamate transporters EAAT-1 and EAAT-2 are decreased in resection specimens from 33 patients with FCD as compared to control tissues. The findings are well described, adequately controlled, and nicely illustrated, and they provide new insight into epileptogenesis of FCD patients, because increased extracellular glutamate levels due to decreased astrocytic uptake may promote seizure activity. Future studies will analyze whether expression and distribution of these and other glutamate transporters are related to clinical features.

Werner Paulus

Muenster, Germany

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ulu, M.O., Tanriverdi, T., Oz, B. et al. The expression of astroglial glutamate transporters in patients with focal cortical dysplasia: an immunohistochemical study. Acta Neurochir 152, 845–853 (2010). https://doi.org/10.1007/s00701-009-0548-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00701-009-0548-2

Keywords

Navigation