Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Astrocyte metabolism and signaling during brain ischemia

Abstract

Brain ischemia results from cardiac arrest, stroke or head trauma. These conditions can cause severe brain damage and are a leading cause of death and long-term disability. Neurons are far more susceptible to ischemic damage than neighboring astrocytes, but astrocytes have diverse and important functions in many aspects of ischemic brain damage. Here we review three main roles of astrocytes in ischemic brain damage. First, we consider astrocyte glycogen stores, which can defend the brain against hypoglycemic brain damage but may aggravate brain damage during ischemia due to enhanced lactic acidosis. Second, we review recent breakthroughs in understanding astrocytic mechanisms of transmitter release, particularly for those transmitters with known roles in ischemic brain damage: glutamate, D-serine, ATP and adenosine. Third, we discuss the role of gap-junctionally connected networks of astrocytes in mediating the spread of damaging molecules to healthy 'bystanders' during infarct expansion in stroke.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Events in brain ischemia.
Figure 2: Simulated ischemia affects three aspects of glutamatergic signaling.
Figure 3: Summary diagram of the processes in neurons and astrocytes which have been shown to or could in principle contribute to the rise in [Glu]o and [Ca2+]i.
Figure 4: Expression and operation of Na+-dependent plasma-membrane glutamate transporters.
Figure 5: Schematic illustrations of possible interactions between healthy and dying cells through gap junctions.

Similar content being viewed by others

References

  1. Choi, D.W. & Rothman, S.M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13, 171–182 (1990).

    Article  CAS  PubMed  Google Scholar 

  2. Lipton, P. Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431–1568 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Silver, I.A., Deas, J. & Erecinska, M. Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience 78, 589–601 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Abramov, A.Y., Scorziello, A. & Duchen, M.R. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J. Neurosci. 27, 1129–1138 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lowry, O.H., Passonneau, J.V., Hasselberger, F.X. & Schulz, D.W. Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J. Biol. Chem. 239, 18–30 (1964).

    Article  CAS  PubMed  Google Scholar 

  6. Hansen, A.J. & Nedergaard, M. Brain ion homeostasis in cerebral ischemia. Neurochem. Pathol. 9, 195–209 (1988).

    CAS  PubMed  Google Scholar 

  7. Kraig, R.P., Ferreira-Filho, C.R. & Nicholson, C. Alkaline and acid transients in cerebellar microenvironment. J. Neurophysiol. 49, 831–850 (1983).

    Article  CAS  PubMed  Google Scholar 

  8. Phillis, J.W., Smith-Barbour, M. & O'Regan, M.H. Changes in extracellular amino acid neurotransmitters and purines during and following ischemias of different durations in the rat cerebral cortex. Neurochem. Int. 29, 115–120 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Rossi, D.J., Oshima, T. & Attwell, D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403, 316–321 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Schubert, P., Keller, F., Nakamura, Y. & Rudolphi, K. The use of ion-sensitive electrodes and fluorescence imaging in hippocampal slices for studying pathological changes of intracellular Ca2+ regulation. J. Neural Transm. Suppl. 44, 73–85 (1994).

    CAS  PubMed  Google Scholar 

  11. Duffy, S. & MacVicar, B.A. In vitro ischemia promotes calcium influx and intracellular calcium release in hippocampal astrocytes. J. Neurosci. 16, 71–81 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Arundine, M. & Tymianski, M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell. Mol. Life Sci. 61, 657–668 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Nicholls, D.G., Johnson-Cadwell, L., Vesce, S., Jekabsons, M., & Yadava, N. Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J. Neurosci. Res. 23 April 2007 (doi:10.1002/jnr.21290).

    Article  CAS  PubMed  Google Scholar 

  14. Pulsinelli, W.A. Selective neuronal vulnerability: morphological and molecular characteristics. Prog. Brain Res. 63, 29–37 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. Higuchi, T., Takeda, Y., Hashimoto, M., Nagano, O. & Hirakawa, M. Dynamic changes in cortical NADH fluorescence and direct current potential in rat focal ischemia: relationship between propagation of recurrent depolarization and growth of the ischemic core. J. Cereb. Blood Flow Metab. 22, 71–79 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Nedergaard, M. & Hansen, A.J. Characterization of cortical depolarizations evoked in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 13, 568–574 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Feustel, P.J., Jin, Y. & Kimelberg, H.K. Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra. Stroke 35, 1164–1168 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Xie, M., Wang, W., Kimelberg, H.K. & Zhou, M. Oxygen and glucose deprivation-induced changes in astrocyte membrane potential and their underlying mechanisms in acute rat hippocampal slices. J. Cereb. Blood Flow Metab. 22 August 2007 (doi:10.1038/5j.jcbfm.9600545).

  19. Brown, A.M. Brain glycogen re-awakened. J. Neurochem. 89, 537–552 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Suh, S.W. et al. Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide). J. Pharmacol. Exp. Ther. 321, 45–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Brown, A.M. et al. Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter. J. Neurosci. Res. 79, 74–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Ransom, B.R. & Fern, R. Does astrocytic glycogen benefit axon function and survival in CNS white matter during glucose deprivation? Glia 21, 134–141 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Magistretti, P.J. Neuron-glia metabolic coupling and plasticity. J. Exp. Biol. 209, 2304–2311 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Tekkok, S.B., Brown, A.M., Westenbroek, R., Pellerin, L. & Ransom, B.R. Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J. Neurosci. Res. 81, 644–652 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Silver, I.A. & Erecinska, M. Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J. Neurosci. 14, 5068–5076 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lindsberg, P.J. & Roine, R.O. Hyperglycemia in acute stroke. Stroke 35, 363–364 (2004).

    Article  PubMed  Google Scholar 

  27. Folbergrova, J., Li, P.A., Uchino, H., Smith, M.L. & Siesjo, B.K. Changes in the bioenergetic state of rat hippocampus during 2.5 min of ischemia, and prevention of cell damage by cyclosporin A in hyperglycemic subjects. Exp. Brain Res. 114, 44–50 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Li, P.A., Kristian, T., Shamloo, M. & Siesjo, K. Effects of preischemic hyperglycemia on brain damage incurred by rats subjected to 2.5 or 5 minutes of forebrain ischemia. Stroke 27, 1592–1601 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Li, P.A., Shamloo, M., Katsura, K., Smith, M.L. & Siesjo, B.K. Critical values for plasma glucose in aggravating ischaemic brain damage: correlation to extracellular pH. Neurobiol. Dis. 2, 97–108 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Li, P.A. & Siesjo, B.K. Role of hyperglycaemia-related acidosis in ischaemic brain damage. Acta Physiol. Scand. 161, 567–580 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Schurr, A. Bench-to-bedside review: a possible resolution of the glucose paradox of cerebral ischemia. Crit. Care 6, 330–334 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Chesler, M. Failure and function of intracellular pH regulation in acute hypoxic-ischemic injury of astrocytes. Glia 50, 398–406 (2005).

    Article  PubMed  Google Scholar 

  33. Xiong, Z.G. et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687–698 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Uyttenboogaart, M. et al. Moderate hyperglycaemia is associated with favourable outcome in acute lacunar stroke. Brain 130, 1626–1630 (2007).

    Article  PubMed  Google Scholar 

  35. Dawson, D.A., Wadsworth, G. & Palmer, A.M. A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke. Brain Res. 892, 344–350 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Devuyst, G. & Bogousslavsky, J. Update on recent progress in drug treatment for acute ischemic stroke. J. Neurol. 248, 735–742 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Lo, E.H., Singhal, A.B., Torchilin, V.P. & Abbott, N.J. Drug delivery to damaged brain. Brain Res. Brain Res. Rev. 38, 140–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Chen, H.S. & Lipton, S.A. The chemical biology of clinically tolerated NMDA receptor antagonists. J. Neurochem. 97, 1611–1626 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Astrup, J., Symon, L., Branston, N.M. & Lassen, N.A. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke 8, 51–57 (1977).

    Article  CAS  PubMed  Google Scholar 

  40. Katchman, A.N. & Hershkowitz, N. Early anoxia-induced vesicular glutamate release results from mobilization of calcium from intracellular stores. J. Neurophysiol. 70, 1–7 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Haydon, P.G. & Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009–1031 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Montana, V., Malarkey, E.B., Verderio, C., Matteoli, M. & Parpura, V. Vesicular transmitter release from astrocytes. Glia 54, 700–715 (2006).

    Article  PubMed  Google Scholar 

  43. Gallagher, C.J. & Salter, M.W. Differential properties of astrocyte calcium waves mediated by P2Y1 and P2Y2 receptors. J. Neurosci. 23, 6728–6739 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Queiroz, G., Meyer, D.K., Meyer, A., Starke, K. & von Kügelgen, I. A study of the mechanism of the release of ATP from rat cortical astroglial cells evoked by activation of glutamate receptors. Neuroscience 91, 1171–1181 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Bal-Price, A., Moneer, Z. & Brown, G.C. Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. Glia 40, 312–323 (2002).

    Article  PubMed  Google Scholar 

  46. Melani, A. et al. ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem. Int. 47, 442–448 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Parkinson, F.E. & Xiong, W. Stimulus- and cell-type-specific release of purines in cultured rat forebrain astrocytes and neurons. J. Neurochem. 88, 1305–1312 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Duan, S. et al. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J. Neurosci. 23, 1320–1328 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Parpura, V., Scemes, E. & Spray, D.C. Mechanisms of glutamate release from astrocytes: gap junction “hemichannels”, purinergic receptors and exocytotic release. Neurochem. Int. 45, 259–264 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Lammer, A. et al. Neuroprotective effects of the P2 receptor antagonist PPADS on focal cerebral ischaemia-induced injury in rats. Eur. J. Neurosci. 23, 2824–2828 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Rudolphi, K.A., Schubert, P., Parkinson, F.E. & Fredholm, B.B. Neuroprotective role of adenosine in cerebral ischaemia. Trends Pharmacol. Sci. 13, 439–445 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Martin, E.D. et al. Adenosine released by astrocytes contributes to hypoxia-induced modulation of synaptic transmission. Glia 55, 36–45 (2007).

    Article  PubMed  Google Scholar 

  53. Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10, 331–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Fiacco, T.A. & McCarthy, K.D. Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J. Neurosci. 24, 722–732 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu, Y. et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27, 2846–2857 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hua, X. et al. Ca2+-dependent glutamate release involves two classes of endoplasmic reticulum Ca2+ stores in astrocytes. J. Neurosci. Res. 76, 86–97 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Montana, V., Ni, Y., Sunjara, V., Hua, X. & Parpura, V. Vesicular glutamate transporter-dependent glutamate release from astrocytes. J. Neurosci. 24, 2633–2642 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fiacco, T.A. et al. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54, 611–626 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Pascual, O. et al. Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Danbolt, N.C. Glutamate uptake. Prog. Neurobiol. 65, 1–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Phillis, J.W., Ren, J. & O'Regan, M.H. Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-threo-β-benzyloxyaspartate. Brain Res. 868, 105–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Jabaudon, D. et al. Inhibition of uptake unmasks rapid extracellular turnover of glutamate of nonvesicular origin. Proc. Natl. Acad. Sci. USA 96, 8733–8738 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cavelier, P. & Attwell, D. Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices. J. Physiol. (Lond.) 564, 397–410 (2005).

    Article  CAS  Google Scholar 

  65. Takahashi, M. et al. The role of glutamate transporters in glutamate homeostasis in the brain. J. Exp. Biol. 200, 401–409 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Ottersen, O.P., Laake, J.H., Reichelt, W., Haug, F.M. & Torp, R. Ischemic disruption of glutamate homeostasis in brain: quantitative immunocytochemical analyses. J. Chem. Neuroanat. 12, 1–14 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Choi, D.W., Maulucci-Gedde, M. & Kriegstein, A.R. Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7, 357–368 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hamann, M., Rossi, D.J., Marie, H. & Attwell, D. 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, 308–314 (2002).

    Article  PubMed  Google Scholar 

  69. Hamann, M., Rossi, D.J., Mohr, C., Andrade, A.L. & Attwell, D. The electrical response of cerebellar Purkinje neurons to simulated ischaemia. Brain 128, 2408–2420 (2005).

    Article  PubMed  Google Scholar 

  70. Mitani, A. & Tanaka, K. Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1. J. Neurosci. 23, 7176–7182 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ouyang, Y.B., Voloboueva, L.A., Xu, L.J. & Giffard, R.G. Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J. Neurosci. 27, 4253–4260 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gebhardt, C., Korner, R. & Heinemann, U. Delayed anoxic depolarizations in hippocampal neurons of mice lacking the excitatory amino acid carrier 1. J. Cereb. Blood Flow Metab. 22, 569–575 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Gorovits, R., Avidan, N., Avisar, N., Shaked, I. & Vardimon, L. Glutamine synthetase protects against neuronal degeneration in injured retinal tissue. Proc. Natl. Acad. Sci. USA 94, 7024–7029 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rao, V.L. et al. Antisense knockdown of the glial glutamate transporter GLT-1, but not the neuronal glutamate transporter EAAC1, exacerbates transient focal cerebral ischemia-induced neuronal damage in rat brain. J. Neurosci. 21, 1876–1883 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang, M. et al. The upregulation of glial glutamate transporter-1 participates in the induction of brain ischemic tolerance in rats. J. Cereb. Blood Flow Metab. 27, 1352–1368 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Rothstein, J.D. et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Shaked, I., Ben Dror, I. & Vardimon, L. Glutamine synthetase enhances the clearance of extracellular glutamate by the neural retina. J. Neurochem. 83, 574–580 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Hoshi, A., Nakahara, T., Kayama, H. & Yamamoto, T. Ischemic tolerance in chemical preconditioning: possible role of astrocytic glutamine synthetase buffering glutamate-mediated neurotoxicity. J. Neurosci. Res. 84, 130–141 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Kimelberg, H.K. Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia 50, 389–397 (2005).

    Article  PubMed  Google Scholar 

  80. Kimelberg, H.K., Goderie, S.K., Higman, S., Pang, S. & Waniewski, R.A. Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J. Neurosci. 10, 1583–1591 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Seki, Y., Feustel, P.J., Keller, R.W. Jr., Tranmer, B.I. & Kimelberg, H.K. Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker. Stroke 30, 433–440 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Abdullaev, I.F., Rudkouskaya, A., Schools, G.P., Kimelberg, H.K. & Mongin, A.A. Pharmacological comparison of swelling-activated excitatory amino acid release and Cl currents in cultured rat astrocytes. J. Physiol. (Lond.) 572, 677–689 (2006).

    Article  CAS  Google Scholar 

  83. Martineau, M., Baux, G. & Mothet, J.P. D-Serine signalling in the brain: friend and foe. Trends Neurosci. 29, 481–491 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Wolosker, H. D-Serine regulation of NMDA receptor activity. Sci. STKE [online] 2006, e41 (2006).

    Google Scholar 

  85. Contreras, J.E. et al. Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Res. Brain Res. Rev. 47, 290–303 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Connors, B.W. & Long, M.A. Electrical synapses in the mammalian brain. Annu. Rev. Neurosci. 27, 393–418 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Thompson, R.J., Zhou, N. & MacVicar, B.A. Ischemia opens neuronal gap junction hemichannels. Science 312, 924–927 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Ye, Z.C., Wyeth, M.S., Baltan-Tekkok, S. & Ransom, B.R. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J. Neurosci. 23, 3588–3596 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Contreras, J.E. et al. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc. Natl. Acad. Sci. USA 99, 495–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Cotrina, M.L. et al. Astrocytic gap junctions remain open during ischemic conditions. J. Neurosci. 18, 2520–2537 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rana, S. & Dringen, R. Gap junction hemichannel-mediated release of glutathione from cultured rat astrocytes. Neurosci. Lett. 415, 45–48 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Lin, J.H.-C. et al. Gap-junction-mediated propagation and amplification of cell injury. Nat. Neurosci. 1, 494–500 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Martins-Ferreira, H., Nedergaard, M. & Nicholson, C. Perspectives on spreading depression. Brain Res. Brain Res. Rev. 32, 215–234 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Rawanduzy, A., Hansen, A., Hansen, T.W. & Nedergaard, M. Effective reduction of infarct volume by gap junction blockade in a rodent model of stroke. J. Neurosurg. 87, 916–920 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Wygoda, M.R. et al. Protection of herpes simplex virus thymidine kinase-transduced cells from ganciclovir-mediated cytotoxicity by bystander cells: the Good Samaritan effect. Cancer Res. 57, 1699–1703 (1997).

    CAS  PubMed  Google Scholar 

  96. Andrade-Rozental, A.F. et al. Gap junctions: the “kiss of death” and the “kiss of life”. Brain Res. Brain Res. Rev. 32, 308–315 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Cusato, K. et al. Gap junctions mediate bystander cell death in developing retina. J. Neurosci. 23, 6413–6422 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Herve, J.C., Bourmeyster, N., Sarrouilhe, D. & Duffy, H.S. Gap junctional complexes: From partners to functions. Prog. Biophys. Mol. Biol. 94, 29–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Figiel, M., Allritz, C., Lehmann, C. & Engele, J. Gap junctional control of glial glutamate transporter expression. Mol. Cell. Neurosci. 35, 130–137 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Lin, J.H. et al. Connexin mediates gap junction-independent resistance to cellular injury. J. Neurosci. 23, 430–441 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank D. Attwell for discussions. This work was supported by US National Institutes of Health grant 5R01NS051561.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David J Rossi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rossi, D., Brady, J. & Mohr, C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci 10, 1377–1386 (2007). https://doi.org/10.1038/nn2004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn2004

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing