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Short-term hypoxia induces a selective death of GABAergic neurons

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Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

It is known that brief episodes of hypoxia protect neurons from death caused by global ischemia and hypoxia (hypoxic preconditioning). At the same time, brief hypoxia may cause a phenomenon of posthypoxic hyperexcitability during reoxygenation, which can lead to the death of separate neurons due to their individual differences. In this work we compare the effects of short-term hypoxia on the initiation of preconditioning and posthypoxic hyperexcitability in two populations of neurons: inhibitory GABAergic neurons and excitatory glutamatergic neurons. Preconditioning effect was evaluated according to the suppression of the NMDA-receptor activity. The phenomenon of posthypoxic hyperexcitability was estimated by the appearance of spontaneous synchronized Ca2+ spikes in the neuronal network during reoxygenation after each episode of hypoxia. It is shown that the preconditioning effect occurs only in glutamatergic neurons. In the GABAergic neurons the effect of preconditioning was not observed. The activity of NMDA receptors in these neurons was not suppressed but increased after each episode of hypoxia. At the moment of posthypoxic synchronous Ca2+-spike generation, a global increase of the cytoplasmic Ca2+ concentration occurred in a few of GABAergic neurons, followed by the apoptotic death of these cells. The anti-inflammatory cytokine, interleukin-10 (IL-10) prevented the development of posthypoxic hyperexcitability, inhibiting spontaneous synchronous Ca2+ spike, and protected GABAergic neurons from the death, restoring the preconditioning effect in them. PI3-kinase inhibitors wortmannin and LY294002 prevented the IL-10 protective effect abolishing the inhibiting effect of IL-10 on the generation of the Ca2+ synchronous spike. These findings point out to the leading role of GABAergic neurons in the development of posthypoxic hyperexcitability. We suggest that the reason for posthypoxic hyperexcitability in the network is a weakening of the inhibiting effect of GABAergic neurons. Activation of different signaling pathways leading to activation of PKB- and PKG-dependent phosphorylation in the neurons of this type represents a possible strategy to protect neurons from death during hypoxia.

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Abbreviations

NMDA:

N-methyl-D-aspartate

GABA:

gamma-aminobutyric acid

PI3K:

phosphoinositide 3-kinase

DIV:

days in vitro

U73122:

inhibitor of phospholipase C

GAD65/67:

glutamate decarboxylase 65/67

ROS:

reactive oxygen species

NOS:

NO synthase

PLC:

phospholipase C

IP3:

inositol trisphosphate

References

  1. Siesj B.K. 1986. Calcium and ischemic brain damage. Eur. Neurol. 25(1), 45–56.

    Article  Google Scholar 

  2. Choi D.W. Glutamate neurotoxicity in cortical cell culture is calcium dependent. 1985. Neurosci. Lett. 58(3), 293–297.

    Article  CAS  PubMed  Google Scholar 

  3. Friedman L.K. 2006. Calcium: A role for neuroprotection and sustained adaptation. Mol. Intervations. 6(6), 315–329.

    Article  Google Scholar 

  4. Heurteaux C., Lauritzen I., Widmann C., Lazdunski M. 1995. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning. Proc. Natl. Acad. Sci. USA. 92, 4666–4670.

    Article  CAS  PubMed  Google Scholar 

  5. Kumral A., Baskin H., Gokmen N., Yilmaz O., Genc K., Genc S., Tatli M.M., Duman N., Ozer E., Ozkan H. 2004. Selective inhibition of nitric oxide in hypoxicischemic brain model in newborn rats: Is it an explanation for the protective role of erythropoietin? Biol. Neonate. 85, 51–54.

    Article  CAS  PubMed  Google Scholar 

  6. Bernaudin M., Tang Y., Reilly M., Petit E., Sharp F.R. 2002. Brain genomic response following hypoxia and re-oxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. J. Biol. Chem. 277, 39728–39738.

    Article  CAS  PubMed  Google Scholar 

  7. Bergeron M., Gidday J.M., Yu A.Y., Semenza G.L., Ferriero D.M., Sharp F.R. 2000. Role of hypoxiainducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann. Neurol. 48, 285–296.

    Article  CAS  PubMed  Google Scholar 

  8. Bond A., Lodge D., Hicks C.A., Ward M.A., O’Neill M.J. 1999. NMDA receptor antagonism, but not AMPA receptor antagonism attenuates induced ischaemic tolerance in the gerbil hippocampus. Eur. J. Pharmacol. 380, 91–99.

    Article  CAS  PubMed  Google Scholar 

  9. Godukhin O.V., Savin A.S., Kalemenev S., Levin S. 2002. Neuronal hyperexcitability induced by repeated brief episodes of hypoxia in rat hippocampal slices: Involvement of ionotropic glutamate receptors and L-type Ca2+ channels. Neuropharmacol. 42, 459–466.

    Article  CAS  Google Scholar 

  10. Levin S.G., Godukhin O.V. 2009. Comparative roles of ATP-sensitive K+ channels and Ca2+-activated BK+-channels in posthypoxic hyperexcitability and rapid hypoxic preconditioning in hippocampal CA1 pyramidal neurons in vitro. Neurosci. Lett. 461, 90–94.

    Article  CAS  PubMed  Google Scholar 

  11. Turovskaya M.V., Turovsky E.A., Zinchenko V.P., Levin S.G., Shamsutdinova A.A., Godukhin O.V. 2011. Repeated brief episodes of hypoxia modulate the calcium responses of ionotropic glutamate receptors in hippocampal neurons. Neurosci. Lett. 496, 11–14.

    Article  CAS  PubMed  Google Scholar 

  12. Turovskaya M.V., Turovsky E.A., Zinchenko V.P., Levin S.G., Godukhin O.V. 2012. Interleukin-10 modulates [Ca2+]i response induced by repeated NMDA receptor activation with brief hypoxia through inhibition of InsP3-sensitive internal stores in hippocampal neurons. Neurosci. Lett. 516(1), 151–155.

    Article  CAS  PubMed  Google Scholar 

  13. Bachis A., Colangelo A.M., Vicini S., Doe P.P., De Bernardi M.A., Brooker G., Mocchetti I. 2001. Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J. Neurosci. 21(9), 3104–3112.

    CAS  PubMed  Google Scholar 

  14. Qian L., Block M.L., Wei S.J., Lin C., Reece J., Pang H., Wilson B., Hong J.S., Flood P.M. 2006. Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. J. Pharmacol. Exp. Ther. 319(1), 44–52.

    Article  CAS  PubMed  Google Scholar 

  15. Sharma S., Yang B., Xi X., Grotta J.C., Aronowski J., Savitz S.I. 2011. IL-10 directly protects cortical neurons by activating PI-3 kinase and STAT-3 pathways. Brain Res. 1373, 189–194.

    Article  CAS  PubMed  Google Scholar 

  16. Belousov A.B. Godfraind J.M., Krnjevic K. 1995. Internal Ca2+ stores involved in anoxic responses of rat hippocampal neurons. J. Physiol. 486(3), 547–556.

    CAS  PubMed  Google Scholar 

  17. Brewer G.J., Torricelli J.R., Evege E.K., Price P.J. 1993. Optimized survival of hippocampal neurons in B27-supplemental neurobasal, a new serum-free medium combination. J. Neurosci. Res. 35, 567–576.

    Article  CAS  PubMed  Google Scholar 

  18. Kononov A.V., Bal’ N.V., and Zinchenko V.P. 2012. Control of spontaneous synchronous Ca2+ oscillations in hippocampal neurons by GABAergic neurons containing kainate receptors without desensitization. Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology. 6(2), 215–220.

    Article  Google Scholar 

  19. Kristian T., Siesjo B.K. 1998. Calcium in ischemic cell death. Stroke. 29, 705–718.

    Article  CAS  PubMed  Google Scholar 

  20. Bonde C., Noraberg J., Noer H., Zimmer J. 2005. Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygenglucose deprivation of hippocampal slice cultures. Neurosci. 136(3), 779–794.

    Article  CAS  Google Scholar 

  21. Rivollier A., Perrin-Cocon L., Luche S., Diemer H., Strub J.M., Hanau D., van Dorsselaer A., Lotteau V., Rabourdin-Combe C., Rabilloud T., Servet-Delprat C. 2006. High expression of antioxidant proteins in dendritic cells: Possible implications in atherosclerosis. Mol. Cell Proteomics. 5(4), 726–736.

    Article  CAS  PubMed  Google Scholar 

  22. Lynch G., Baudry M. 1984. The biochemistry of memory: A new and specific hypothesis. Science. 224(4653), 1057–1063.

    Article  CAS  PubMed  Google Scholar 

  23. Alexi T., Borlongan C.V., Faull R.L.M., Williams C.E., Clark R.G., Gluckman P.D., Hughes P.E. 2000. Neuroprotective strategies for basal ganglia degeneration: Parkinson’s and Huntington’s diseases. Progr. Neurobiol. 60, 409–470.

    Article  CAS  Google Scholar 

  24. Simonian N.A., Coyle J.T. 1996. Oxidative stress in neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. 36, 83–106.

    Article  CAS  PubMed  Google Scholar 

  25. Cassarino D.S., Bennett J.P. Jr. 1999. An evaluation of the role of mitochondria in neurodegenerative diseases: Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res. Rev. 29(1), 1–25.

    Article  CAS  PubMed  Google Scholar 

  26. Kruman I., Bruce-Keller A.J., Bredesen D., Waeg G., Mattson M.P. 1997. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci. 17(13), 5089–5100.

    CAS  PubMed  Google Scholar 

  27. Choi D.W., Peters S., Viseskul V. 1987. Dextrorphan and levorphanol selectively block N-methyl-D-aspartate receptor-mediated neurotoxicity on cortical neurons. J. Pharmacol. Exp. Ther. 242(2), 713–720.

    CAS  PubMed  Google Scholar 

  28. Perez-Pinzon M.A., Mumford P.L., Rosenthal M. 1996. Anoxic preconditioning in hippocampal slices: Role of adenosine. Neurosci. 75, 687–694.

    Article  CAS  Google Scholar 

  29. Tremblay R., Chakravarthy B., Hewitt K., Tauskela J., Morley P., Atkinson T., Durkin J.P. 2000. Transient NMDA receptor inactivation provides long-term protection to cultured cortical neurons from a variety of deaths. J. Neurosci. 20(19), 7183–7192.

    CAS  PubMed  Google Scholar 

  30. Liu J., Ginis I., Spatz M., Hallenbeck J.M. 2000. Hypoxic preconditioning protects cultured neurons against hypoxic stress via TNF-α and ceramide. Am. J. Physiol. Cell. Physiol. 278(1), 144–153.

    Google Scholar 

  31. Wu L.Y., Ding A.S., Zhao T., Ma Z.M., Wang F.Z., Fan M. 2005. Underlying mechanism of hypoxic preconditioning decreasing apoptosis induced by anoxia in cultured hippocampal neurons. Neurosignals. 14(3), 109–116.

    Article  CAS  PubMed  Google Scholar 

  32. Sharp F.R., Ran R., Lu A., Tang Y., Strauss K.I., Glass T., Ardizzone T., Bernaudin M. 2004. Hypoxic preconditioning protects against ischemic brain injury. NeuroRx. 1(1), 26–35.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Jia J., Wang X., Li H., Han S., Zu P., Li J. 2007. Activations of nPKCe and ERK1/2 were involved in oxygenglucose deprivation-induced neuroprotection via NMDA receptors in hippocampal slices of mice. J. Neurosurg. Anesthesiol. 19(1), 18–24.

    Article  PubMed  Google Scholar 

  34. Gidday J.M., Shah A.R., Maceren R.G., Wang Q., Pelligrino D.A., Holtzman D.M., Park T.S. 1999. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J. Cereb. Blood Flow Metab. 19, 331–340.

    Article  CAS  PubMed  Google Scholar 

  35. Gonzalez-Zulueta M., Feldman A.B., Klesse L.J., Kalb R.G., Dillman J.F., Parada L.F., Dawson T.M., Dawson V.L. 2000. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc. Natl. Acad. Sci. USA. 97, 436–441.

    Article  CAS  PubMed  Google Scholar 

  36. Gonzalez-Burgos G., Lewis D.A. 2008. GABA-neurons and the mechanisms of network oscillations: Implications for understanding cortical dysfunction in schizophrenia. Schizophr. Bull. 34(5), 944–961.

    Article  PubMed  Google Scholar 

  37. Earls L.R., Hacker M.L., Watson J.D., Miller D.M. 3rd. 2010. Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration. Proc. Natl. Acad. Sci. USA. 107(32), 14460–14465.

    Article  CAS  PubMed  Google Scholar 

  38. Romijn H.J. 1989. Preferential loss of GABAergic neurons in hypoxia-exposed neocortex slab cultures is attenuated by the NMDA receptor blocker D-2-amino-7-phosphonoheptanoate. Brain Res. 501(1), 100–104.

    Article  CAS  PubMed  Google Scholar 

  39. Romijn H.J., Ruijter J.M., Wolters P.S. 1988. Hypoxia preferentially destroys GABAergic neurons in developing rat neocortex explants in culture. Exp. Neur. 100(2), 332–340.

    Article  CAS  Google Scholar 

  40. Nitsch C., Scotti A., Sommacal A., Kalt G. 1989. GABAergic hippocampal neurons resistant to ischemia-induced neuronal death contain the Ca2+-binding protein parvalbumin. Neurosci. Lett. 105(3), 263–268.

    Article  CAS  PubMed  Google Scholar 

  41. Levin S.G., Godukhin O.V. 2011. Anti-inflammatory cytokines, TGF-β1 and IL-10, exert anti-hypoxic action and abolish posthypoxic hyperexcitability in hippocampal slice neurons: Comparative aspects. Exp. Neur. 232, 329–332.

    Article  CAS  Google Scholar 

  42. Flanders K.C., Ren R.F., Lippa C.F. 1998. Transforming growth factor-βs in neurodegenerative disease. Progr. Neurobiol. 54(1), 71–85.

    Article  CAS  Google Scholar 

  43. Sharma S., Yang B., Xi X., Grotta J.C., Aronowski J., Savitz S.I. 2011. IL-10 directly protects cortical neurons by activating PI3 kinase and STAT-3 pathways. Brain. Res. 1373, 189–194.

    Article  CAS  PubMed  Google Scholar 

  44. Müller M., Felmy F., Schwaller B., Schneggenburger R. 2007. Parvalbumin is a mobile presynaptic Ca2+ buffer in the calyx of held that accelerates the decay of Ca2+ and short-term facilitation. J. Neurosci. 27(9), 2261–2271.

    Article  PubMed  Google Scholar 

  45. Ha K.S., Kim K.M., Kwon Y.G., Bai S.K., Nam W.D., Yoo Y.M., Kim P.K., Chung H.T., Billiar T.R., Kim Y.M. 2003. Nitric oxide prevents 6-hydroxydopamine-induced apoptosis in PC12 cells through cGMP-dependent PI3 kinase/Akt activation. FASEB J. 17, 1036–1047.

    Article  CAS  PubMed  Google Scholar 

  46. Szado T., Vanderheyden V., Parys J.B., De Smedt H., Rietdorf K., Kotelevets L. 2008. Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc. Natl. Acad. Sci. USA. 105, 2427–2432.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Cell Biophysics, Russian Academy of Sciences, ul. Institutskaya, 3, Pushchino, Moscow oblast, 142290, Russia

    M. V. Turovskaya, E. A. Turovsky, A. V. Kononov & V. P. Zinchenko

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  1. M. V. Turovskaya
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  2. E. A. Turovsky
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  3. A. V. Kononov
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  4. V. P. Zinchenko
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Correspondence to V. P. Zinchenko.

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Original Russian Text © M.V. Turovskaya, E.A. Turovsky, A.V. Kononov, V.P. Zinchenko, 2013, published in Biologicheskie Membrany, 2013, Vol. 30, No. 5–6, pp. 479–490.

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Turovskaya, M.V., Turovsky, E.A., Kononov, A.V. et al. Short-term hypoxia induces a selective death of GABAergic neurons. Biochem. Moscow Suppl. Ser. A 8, 125–135 (2014). https://doi.org/10.1134/S199074781305019X

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  • DOI: https://doi.org/10.1134/S199074781305019X

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