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Erythropoietin affects GABAergic transmission in hippocampal neurons in vitro


Erythropoietin is a potent regulator of erythropoiesis. It acts via the specific membrane receptor (EpoR). Erythropoietin is also known to be present in the central nervous system, and its concentration and the expression of EpoR change during development, which raises the possibility that this modulator might be involved in the regulation of neuronal functions in the developing brain. The GABAergic system undergoes profound changes during development and is particularly susceptible to modulation by endogenous factors. Therefore, we decided to investigate the impact of Epo on GABAergic transmission in hippocampal neurons developing in vitro. An analysis of miniature IPSCs (mIPSCs) revealed that a long-term treatment with Epo (48 or 72 h) resulted in a major acceleration of the decaying phase of these currents while the amplitude and current frequency remained unchanged. Interestingly, this effect was restricted to the youngest considered age group (6-8 DIV), indicating that Epomediated modulation of mIPSCs depends on the developmental stage of the neurons. We conclude that Epo may exert a modulatory action on GABAergic transmission in developing neural networks.





gamma aminobutyric acid


miniature inhibitory postsynaptic current


  1. Genc, S., Koroglu, T.F. and Genc, K. Erythropoietin and the nervous system. Brain Res. 1000 (2004) 19–31.

    PubMed  Article  CAS  Google Scholar 

  2. Digicaylioglu, M., Bichet, S., Marti, H.H., Wenger, R.H., Rivas, L.A., Bauer, C. and Gassmann, M. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc. Natl. Acad. Sci. USA 92 (1995) 3717–3720.

    PubMed  Article  CAS  Google Scholar 

  3. Masuda, S., Nagao, M., Takahata, K., Konishi, Y., Gallyas, F. Jr., Tabira, T. and Sasaki, R. Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J. Biol. Chem. 268 (1993) 11208–11216.

    CAS  Google Scholar 

  4. Tan, C.C., Eckardt, K.U., Firth, J.D. and Ratcliffe, P.J. Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am. J. Physiol. 263 (1992) F474–481.

    PubMed  CAS  Google Scholar 

  5. Brines, M.L., Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N.C., Cerami, C., Itri, L.M. and Cerami, A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc. Natl. Acad. Sci. USA 97 (2000) 10526–10531.

    PubMed  Article  CAS  Google Scholar 

  6. Kumral, A., Ozer, E., Yilmaz, O., Akhisaroglu, M., Gokmen, N., Duman, N., Ulukus, C., Genc, S. and Ozkan, H. Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats. Biol. Neonat. 83 (2003) 224–228.

    Article  CAS  Google Scholar 

  7. Buemi, M., Cavallaro, E., Floccari, F., Sturiale, A., Aloisi, C., Trimarchi, M., Grasso, G., Corica, F. and Frisina, N. Erythropoietin and the brain: from neurodevelopment to neuroprotection. Clin. Sci. (Lond) 103 (2002) 275–282.

    CAS  Google Scholar 

  8. Zhang, F., Signore, A.P., Zhou, Z., Wang, S., Cao, G. and Chen, J. Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: potential signaling mechanisms. J. Neurosci. Res. 83 (2006) 1241–1251.

    PubMed  Article  CAS  Google Scholar 

  9. Yang, J., Huang, Y., Yu, X., Sun, H., Li, Y. and Deng, Y. Erythropoietin preconditioning suppresses neuronal death following status epilepticus in rats. Acta Neurobiol. Exp. (Wars) 67 (2007) 141–148.

    Google Scholar 

  10. Ransome, M.I. and Turnley, A.M. Systemically delivered Erythropoietin transiently enhances adult hippocampal neurogenesis. J. Neurochem. 102 (2007) 1953–1965.

    PubMed  Article  CAS  Google Scholar 

  11. Dame, C., Bartmann, P., Wolber, E., Fahnenstich, H., Hofmann, D. and Fandrey, J. Erythropoietin gene expression in different areas of the developing human central nervous system. Brain Res. Dev. Brain Res. 125 (2000) 69–74.

    PubMed  Article  CAS  Google Scholar 

  12. Juul, S. Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta Paediatr. Suppl. 91 (2002) 36–42.

    PubMed  Article  CAS  Google Scholar 

  13. Juul, S.E., Yachnis, A.T., Rojiani, A.M. and Christensen, R.D. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr. Dev. Pathol. 2 (1999) 148–158.

    PubMed  Article  CAS  Google Scholar 

  14. Hollrigel, G.S. and Soltesz, I. Slow kinetics of miniature IPSCs during early postnatal development in granule cells of the dentate gyrus. J. Neurosci. 17 (1997) 5119–5128.

    PubMed  CAS  Google Scholar 

  15. Andjus, P.R., Stevic-Marinkovic, Z. and Cherubini, E. Immunoglobulins from motoneurone disease patients enhance glutamate release from rat hippocampal neurones in culture. J. Physiol. 504 (1997) 103–112.

    PubMed  Article  CAS  Google Scholar 

  16. Pytel, M., Wojtowicz, T., Mercik, K., Sarto-Jackson, I., Sieghart, W., Ikonomidou, C. and Mozrzymas, J.W. 17 beta-estradiol modulates GABAergic synaptic transmission and tonic currents during development in vitro. Neuropharmacology 52 (2007) 1342–1353.

    PubMed  Article  CAS  Google Scholar 

  17. Clements, J.D. Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends. Neurosci. 19 (1996) 163–171.

    PubMed  Article  CAS  Google Scholar 

  18. Mozrzymas, J.W. Dynamism of GABA(A) receptor activation shapes the “personality” of inhibitory synapses. Neuropharmacology 47 (2004) 945–960.

    PubMed  CAS  Article  Google Scholar 

  19. Cherubini, E., Gaiarsa, J.L. and Ben-Ari, Y. GABA: an excitatory transmitter in early postnatal life. Trends. Neurosci. 14 (1991) 515–519.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Tomasz Wójtowicz.

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Wójtowicz, T., Mozrzymas, J.W. Erythropoietin affects GABAergic transmission in hippocampal neurons in vitro . Cell Mol Biol Lett 13, 649–655 (2008).

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Key words

  • GABAA receptors
  • Erythropoietin
  • Miniature post synaptic current mIPSC
  • Neuronal culture