Astrocyte dysfunction in neurological disorders: a molecular perspective (original) (raw)

• Parpura, V. et al. Glutamate-mediated astrocyte–neuron signalling. Nature 369, 744–747 (1994).
  Article CAS PubMed Google Scholar
• Steinhäuser, C., Jabs, R. & Kettenmann, H. Properties of GABA and glutamate responses in identified glial cells of the mouse hippocampal slice. Hippocampus 4, 19–35 (1994).
  Article PubMed Google Scholar
• Jabs, R. et al. Synaptic transmission onto hippocampal glial cells with hGFAP promoter activity. J. Cell Sci. 118, 3791–3803 (2005).
  Article CAS PubMed Google Scholar
• Matthias, K. et al. Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus. J. Neurosci. 23, 1750–1758 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Wallraff, A., Odermatt, B., Willecke, K. & Steinhäuser, C. Distinct types of astroglial cells in the hippocampus differ in gap junction coupling. Glia 48, 36–43 (2004).
  Article PubMed Google Scholar
• Verkhratsky, A. & Steinhäuser, C. Ion channels in glial cells. Brain Res. Rev. 32, 380–412 (2000).
  Article CAS PubMed Google Scholar
• Kettenmann, H. & Steinhäuser, C. In Neuroglia 2nd edn (eds Kettenmann, H. & Ransom, B. R.) 131–145 (Oxford Univ. Press, 2005).
  Google Scholar
• Higashi, K. et al. An inwardly rectifying K+ channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am. J. Physiol. Cell Physiol. 281, C922–C931 (2001).
  Article CAS PubMed Google Scholar
• Verkman, A. S. More than just water channels: unexpected cellular roles of aquaporins. J. Cell Sci. 118, 3225–3232 (2005).
  Article CAS PubMed Google Scholar
• Amiry-Moghaddam, M., Frydenlund, D. S. & Ottersen, O. P. Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience 129, 999–1010 (2004).
  Article CAS PubMed Google Scholar
• Theis, M., Sohl, G., Eiberger, J. & Willecke, K. Emerging complexities in identity and function of glial connexins. Trends Neurosci. 28, 188–195 (2005).
  Article CAS PubMed Google Scholar
• Nedergaard, M., Ransom, B. & Goldman, S. A. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 26, 523–530 (2003).
  Article CAS PubMed Google Scholar
• Danbolt, N. C. Glutamate uptake. Prog. Neurobiol. 65, 1–105 (2001).
  Article CAS PubMed Google Scholar
• Bergles, D. E., Diamond, J. S. & Jahr, C. E. Clearance of glutamate inside the synapse and beyond. Curr. Opin. Neurobiol. 9, 293–298 (1999).
  Article CAS PubMed Google Scholar
• Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Rev. Neurosci. 6, 626–640 (2005).
  Article CAS Google Scholar
• Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003).
  Article CAS PubMed Google Scholar
• Mulligan, S. J. & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004).
  Article CAS PubMed Google Scholar
• Takano, T. et al. Astrocyte-mediated control of cerebral blood flow. Nature Neurosci. 9, 260–267 (2006).
  Article CAS PubMed Google Scholar
• Kim, J. H. Pathology of epilepsy. Exp. Mol. Pathol. 70, 345–367 (2001).
  Article CAS PubMed Google Scholar
• Blümcke, I., Thom, M. & Wiestler, O. D. Ammon's horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy. Brain Pathol. 12, 199–211 (2002).
  PubMed Google Scholar
• De Lanerolle, N. C. & Lee, T. S. New facets of the neuropathology and molecular profile of human temporal lobe epilepsy. Epilepsy Behav. 7, 190–203 (2005).
  Article PubMed Google Scholar
• Kivi, A. et al. Effects of barium on stimulus-induced rises of [K+]o in human epileptic non-sclerotic and sclerotic hippocampal area CA1. Eur. J. Neurosci. 12, 2039–2048 (2000).
  Article CAS PubMed Google Scholar
• Hinterkeuser, S. et al. Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur. J. Neurosci. 12, 2087–2096 (2000). References 22 and 23 show the downregulation of inwardly rectifying K+ currents and the impairment of Ba 2+ -sensitive K+-buffering in the sclerotic hippocampus from epilepsy patients.
  Article CAS PubMed Google Scholar
• Bordey, A. & Sontheimer, H. Properties of human glial cells associated with epileptic seizure foci. Epilepsy Res. 32, 286–303 (1998).
  Article CAS PubMed Google Scholar
• Schröder, W. et al. Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 41, S181–S184 (2000).
  Article PubMed Google Scholar
• Binder, D. K. et al. Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia (in the press).
• Eid, T. et al. Loss of perivascular aquaporin 4 may underlie deficient water and K+ homeostasis in the human epileptogenic hippocampus. Proc. Natl Acad. Sci. USA 102, 1193–1198 (2005). Reports that in patients with AHS the density of AQP4 water channels at perivascular end-feet is reduced. The perturbed water flux through astrocytes entails impaired buffering of extracellular potassium.
  Article CAS PubMed PubMed Central Google Scholar
• Amiry-Moghaddam, M. et al. An α-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc. Natl Acad. Sci. USA 100, 2106–2111 (2003). Using a mouse model with defective anchoring of AQP4 to the cytoskeleton, the authors document the importance of proper subcellular segregation for aquaporin function in astrocytes under ischaemic stress in vivo.
  Article CAS PubMed PubMed Central Google Scholar
• Glass, M. & Dragunow, M. Neurochemical and morphological changes associated with human epilepsy. Brain Res. Rev. 21, 29–41 (1995).
  Article CAS PubMed Google Scholar
• Tanaka, K. et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276, 1699–1702 (1997).
  Article CAS PubMed Google Scholar
• Rothstein, J. D. et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16, 675–686 (1996).
  Article CAS PubMed Google Scholar
• Campbell, S. L. & Hablitz, J. J. Glutamate transporters regulate excitability in local networks in rat neocortex. Neuroscience 127, 625–635 (2004).
  Article CAS PubMed Google Scholar
• Demarque, M. et al. Glutamate transporters prevent the generation of seizures in the developing rat neocortex. J. Neurosci. 24, 3289–3294 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Wong, M. et al. Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann. Neurol. 54, 251–256 (2003).
  Article CAS PubMed Google Scholar
• Tessler, S., Danbolt, N. C., Faull, R. L. M., Storm-Mathisen, J. & Emson, P. C. Expression of the glutamate transporters in human temporal lobe epilepsy. Neuroscience 88, 1083–1091 (1999).
  Article CAS PubMed Google Scholar
• Mathern, G. W. et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52, 453–472 (1999).
  Article CAS PubMed Google Scholar
• Proper, E. A. et al. Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125, 32–43 (2002).
  Article CAS PubMed Google Scholar
• During, M. J. & Spencer, D. D. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341, 1607–1610 (1993).
  Article CAS PubMed Google Scholar
• Eid, T. et al. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 28–37 (2004).
  Article CAS PubMed Google Scholar
• Petroff, O. A., Errante, L. D., Rothman, D. L., Kim, J. H. & Spencer, D. D. Glutamate–glutamine cycling in the epileptic human hippocampus. Epilepsia 43, 703–710 (2002). References 39 and 40 indicate that in epilepsy in humans downregulation of astroglial glutamine synthetase disturbs the conversion of glutamate and its accumulation in the extracellular space.
  Article CAS PubMed Google Scholar
• Rothstein, J. D. et al. β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005). Identifies β-lactam antibiotics as potential therapeutic agents for the treatment of diseases associated with excitotoxic degeneration through upregulation of the astroglial glutamate transporter EAAT2.
  Article CAS PubMed Google Scholar
• Brusa, R. et al. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270, 1677–1680 (1995).
  Article CAS PubMed Google Scholar
• Seifert, G. et al. Changes in flip/flop splicing of astroglial AMPA receptors in human temporal lobe epilepsy. Epilepsia 43 (Suppl. 5), 162–167 (2002).
  Article CAS PubMed Google Scholar
• Seifert, G., Hüttmann, K., Schramm, J. & Steinhäuser, C. Enhanced relative expression of glutamate receptor 1 flip AMPA receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon's horn sclerosis. J. Neurosci. 24, 1996–2003 (2004). The authors show that aberrant AMPA receptor splicing in astrocytes of the sclerotic human hippocampus affects the kinetics of AMPA receptor desensitization, which might contribute to seizure generation.
  Article CAS PubMed PubMed Central Google Scholar
• Schröder, W., Seifert, G., Hüttmann, K., Hinterkeuser, S. & Steinhäuser, C. AMPA receptor-mediated modulation of inward rectifier K+ channels in astrocytes of mouse hippocampus. Mol. Cell Neurosci. 19, 447–458 (2002).
  Article CAS PubMed Google Scholar
• Whitney, K. D. & McNamara, J. O. GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins. J. Neurosci. 20, 7307–7316 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Manning, T. J. Jr & Sontheimer, H. Spontaneous intracellular calcium oscillations in cortical astrocytes from a patient with intractable childhood epilepsy (Rasmussen's encephalitis). Glia 21, 332–337 (1997).
  Article PubMed Google Scholar
• Steinhäuser, C. & Seifert, G. Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur. J. Pharmacol. 447, 227–237 (2002).
  Article PubMed Google Scholar
• Tang, F. R. & Lee, W. L. Expression of the group II and III metabotropic glutamate receptors in the hippocampus of patients with mesial temporal lobe epilepsy. J. Neurocytol. 30, 137–143 (2001).
  Article CAS PubMed Google Scholar
• Aronica, E. et al. Expression and cell distribution of group I and group II metabotropic glutamate receptor subtypes in taylor-type focal cortical dysplasia. Epilepsia 44, 785–795 (2003).
  Article CAS PubMed Google Scholar
• Aronica, E. et al. Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur. J. Neurosci. 17, 2106–2118 (2003).
  Article PubMed Google Scholar
• Kang, N., Xu, J., Xu, Q., Nedergaard, M. & Kang, J. Astrocytic glutamate release-induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 94, 4121–4130 (2005).
  Article CAS PubMed Google Scholar
• Tian, G. F. et al. An astrocytic basis of epilepsy. Nature Med. 11, 973–981 (2005). Reports that, in acute epilepsy models, glutamate released from astrocytes causes paroxysmal depolarization shifts in neurons. Several antiepileptic drugs were shown to reduce astrocytic [Ca 2+]i elevations and therefore astrocytes might be considered as new targets for antiepileptic treatments.
  Article CAS PubMed Google Scholar
• Rothstein, J. D., Martin, L. J. & Kuncl, R. W. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N. Engl. J. Med. 326, 1464–1468 (1992).
  Article CAS PubMed Google Scholar
• Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J. & Kuncl, R. W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73–84 (1995). References 54 and 55 describe the loss of glial glutamate transporters in ALS and identify astrocytes as crucial mediators of excitotoxicity and motor neuron loss.
  Article CAS PubMed Google Scholar
• Sasaki, S., Komori, T. & Iwata, M. Excitatory amino acid transporter 1 and 2 immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol. (Berl.) 100, 138–144 (2000).
  Article CAS Google Scholar
• Yamada, K. et al. Glutamate transporter GLT-1 is transiently localized on growing axons of the mouse spinal cord before establishing astrocytic expression. J. Neurosci. 18, 5706–5713 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Schmitt, A., Asan, E., Puschel, B., Jons, T. & Kugler, P. Expression of the glutamate transporter GLT1 in neural cells of the rat central nervous system: non-radioactive in situ hybridization and comparative immunocytochemistry. Neuroscience 71, 989–1004 (1996).
  Article CAS PubMed Google Scholar
• Lin, C. L. et al. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20, 589–602 (1998). Shows that in patients with ALS, loss of astroglial EAAT2 is due to aberrant RNA splicing.
  Article CAS PubMed Google Scholar
• Meyer, T. et al. The RNA of the glutamate transporter EAAT2 is variably spliced in amyotrophic lateral sclerosis and normal individuals. J. Neurol. Sci. 170, 45–50 (1999).
  Article CAS PubMed Google Scholar
• Honig, L. S., Chambliss, D. D., Bigio, E. H., Carroll, S. L. & Elliott, J. L. Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls. Neurology 55, 1082–1088 (2000).
  Article CAS PubMed Google Scholar
• Volterra, A., Trotti, D., Tromba, C., Floridi, S. & Racagni, G. Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J. Neurosci. 14, 2924–2932 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993). First report that mutation of the Cu/Zn superoxide dismutase ( SOD1 ) gene mediates neurodegeneration in hereditary ALS.
  Article CAS PubMed Google Scholar
• Trotti, D., Rolfs, A., Danbolt, N. C., Brown, R. H. Jr & Hediger, M. A. SOD1 mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nature Neurosci. 2, 427–433 (1999). Shows that mutant SOD1 leads to neurotoxicity through inactivation of the astroglial glutamate transporter EAAT2.
  Article CAS PubMed Google Scholar
• Howland, D. S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl Acad. Sci. USA 99, 1604–1609 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Bruijn, L. I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327–338 (1997).
  Article CAS PubMed Google Scholar
• Pedersen, W. A. et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann. Neurol. 44, 819–824 (1998).
  Article CAS PubMed Google Scholar
• Bruijn, L. I., Miller, T. M. & Cleveland, D. W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749 (2004).
  Article CAS PubMed Google Scholar
• Pramatarova, A., Laganiere, J., Roussel, J., Brisebois, K. & Rouleau, G. A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369–3374 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Lino, M. M., Schneider, C. & Caroni, P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22, 4825–4832 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Gong, Y. H., Parsadanian, A. S., Andreeva, A., Snider, W. D. & Elliott, J. L. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20, 660–665 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003).
  Article CAS PubMed Google Scholar
• Urushitani, M. et al. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nature Neurosci. 9, 108–118 (2006). Suggests that, in ALS, astrocytes contribute to the secretion of mutant SOD1, which, in turn, produces microgliosis and motor neuron death.
  Article CAS PubMed Google Scholar
• Rao, S. D., Yin, H. Z. & Weiss, J. H. Disruption of glial glutamate transport by reactive oxygen species produced in motor neurons. J. Neurosci. 23, 2627–2633 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Rao, S. D. & Weiss, J. H. Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis. Trends Neurosci. 27, 17–23 (2004).
  Article CAS PubMed Google Scholar
• Levine, J. B., Kong, J. M., Nadler, M. & Xu, Z. S. Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia 28, 215–224 (1999).
  Article CAS PubMed Google Scholar
• Almer, G. et al. Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann. Neurol. 49, 176–185 (2001).
  Article CAS PubMed Google Scholar
• Yasojima, K., Tourtellotte, W. W., McGeer, E. G. & McGeer, P. L. Marked increase in cyclooxygenase-2 in ALS spinal cord: implications for therapy. Neurology 57, 952–956 (2001).
  Article CAS PubMed Google Scholar
• Yamagata, K., Andreasson, K. I., Kaufmann, W. E., Barnes, C. A. & Worley, P. F. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11, 371–386 (1993).
  Article CAS PubMed Google Scholar
• Pepicelli, O. et al. In vivo activation of _N_-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E2 extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms. J. Neurochem. 81, 1028–1034 (2002).
  Article CAS PubMed Google Scholar
• Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998).
  Article CAS PubMed Google Scholar
• Drachman, D. B. et al. Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann. Neurol. 52, 771–778 (2002).
  Article CAS PubMed Google Scholar
• Aronica, E., Catania, M. V., Geurts, J., Yankaya, B. & Troost, D. Immunohistochemical localization of group I and II metabotropic glutamate receptors in control and amyotrophic lateral sclerosis human spinal cord: upregulation in reactive astrocytes. Neuroscience 105, 509–520 (2001).
  Article CAS PubMed Google Scholar
• Catania, M. V., Aronica, E., Yankaya, B. & Troost, D. Increased expression of neuronal nitric oxide synthase spliced variants in reactive astrocytes of amyotrophic lateral sclerosis human spinal cord. J. Neurosci. 21, RC148 (2001). Suggests that in human ALS aberrant expression of neuronal NOS in reactive astrocytes is involved in pathogenesis.
  Article CAS PubMed PubMed Central Google Scholar
• Trotti, D. et al. Peroxynitrite inhibits glutamate transporter subtypes. J. Biol. Chem. 271, 5976–5979 (1996).
  Article CAS PubMed Google Scholar
• Beal, M. F. et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann. Neurol. 42, 644–654 (1997).
  Article CAS PubMed Google Scholar
• Bruno, V. et al. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J. Cereb. Blood Flow Metab. 21, 1013–1033 (2001).
  Article CAS PubMed Google Scholar
• Amiry-Moghaddam, M. et al. α-Syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood–brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J. 18, 542–544 (2004).
  Article CAS PubMed Google Scholar
• Manley, G. T. et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nature Med. 6, 159–163 (2000).
  Article CAS PubMed Google Scholar
• Lo, A. C. et al. Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet. J. Cereb. Blood Flow Metab. 25, 998–1011 (2005).
  Article CAS PubMed Google Scholar
• Da, T. & Verkman, A. S. Aquaporin-4 gene disruption in mice protects against impaired retinal function and cell death after ischemia. Invest. Ophthalmol. Vis. Sci. 45, 4477–4483 (2004).
  Article PubMed Google Scholar
• Dalloz, C. et al. Targeted inactivation of dystrophin gene product Dp71: phenotypic impact in mouse retina. Hum. Mol. Genet. 12, 1543–1554 (2003).
  Article CAS PubMed Google Scholar
• Hibino, H., Fujita, A., Iwai, K., Yamada, M. & Kurachi, Y. Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes. J. Biol. Chem. 279, 44065–44073 (2004).
  Article CAS PubMed Google Scholar
• Thomzig, A. et al. Kir6.1 is the principal pore-forming subunit of astrocyte but not neuronal plasma membrane K–ATP channels. Mol. Cell. Neurosci. 18, 671–690 (2001).
  Article CAS PubMed Google Scholar
• Stonehouse, A. H. et al. Characterisation of Kir2.0 proteins in the rat cerebellum and hippocampus by polyclonal antibodies. Histochem. Cell Biol. 112, 457–465 (1999).
  Article CAS PubMed Google Scholar
• Farahani, R. et al. Alterations in metabolism and gap junction expression may determine the role of astrocytes as 'good samaritans' or executioners. Glia 50, 351–361 (2005).
  Article PubMed Google Scholar
• Nakase, T., Söhl, G., Theis, M., Willecke, K. & Naus, C. C. Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. Am. J. Pathol. 164, 2067–2075 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Perez Velazquez, J. L., Kokarovtseva, L., Sarbaziha, R., Jeyapalan, Z. & Leshchenko, Y. Role of gap junctional coupling in astrocytic networks in the determination of global ischaemia-induced oxidative stress and hippocampal damage. Eur. J. Neurosci. 23, 1–10 (2006).
  Article PubMed Google Scholar
• Nicchia, G. P. et al. New possible roles for aquaporin-4 in astrocytes: cell cytoskeleton and functional relationship with connexin43. FASEB J. 19, 1674–1676 (2005).
  Article CAS PubMed Google Scholar
• Rozyczka, J., Figiel, M. & Engele, J. Chronic endothelin exposure inhibits connexin43 expression in cultured cortical astroglia. J. Neurosci. Res. 79, 303–309 (2005).
  Article CAS PubMed Google Scholar
• 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
• Takano, T. et al. Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc. Natl Acad. Sci. USA 102, 16466–16471 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• 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
• Fujita, H., Sato, K., Wen, T. C., Peng, Y. & Sakanaka, M. Differential expressions of glycine transporter 1 and three glutamate transporter mRNA in the hippocampus of gerbils with transient forebrain ischemia. J. Cereb. Blood Flow Metab. 19, 604–615 (1999).
  Article CAS PubMed Google Scholar
• Maragakis, N. J. & Rothstein, J. D. Glutamate transporters in neurologic disease. Arch. Neurol. 58, 365–370 (2001).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• Selkirk, J. V. et al. Role of the GLT-1 subtype of glutamate transporter in glutamate homeostasis: the GLT-1-preferring inhibitor WAY-855 produces marginal neurotoxicity in the rat hippocampus. Eur. J. Neurosci. 21, 3217–3228 (2005).
  Article PubMed Google Scholar
• Swanson, R. A. et al. Neuronal regulation of glutamate transporter subtype expression in astrocytes. J. Neurosci. 17, 932–940 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Schluter, K., Figiel, M., Rozyczka, J. & Engele, J. CNS region-specific regulation of glial glutamate transporter expression. Eur. J. Neurosci. 16, 836–842 (2002).
  Article PubMed Google Scholar
• Reagan, L. P. et al. Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc. Natl Acad. Sci. USA 101, 2179–2184 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Zschocke, J. et al. Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. J. Biol. Chem. 280, 34924–34932 (2005).
  Article CAS PubMed Google Scholar
• 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
• Yamamoto-Mizuma, S. et al. Altered properties of volume-sensitive osmolyte and anion channels (VSOACs) and membrane protein expression in cardiac and smooth muscle myocytes from Clcn3 −/− mice. J. Physiol. 557, 439–456 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Jentsch, T. J., Stein, V., Weinreich, F. & Zdebik, A. A. Molecular structure and physiological function of chloride channels. Physiol. Rev. 82, 503–568 (2002).
  Article CAS PubMed Google Scholar
• Kimelberg, H. K. et al. Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuroreport 11, 2675–2679 (2000).
  Article CAS PubMed Google Scholar
• Zhang, Y. et al. Behavioral and histological neuroprotection by tamoxifen after reversible focal cerebral ischemia. Exp. Neurol. 196, 41–46 (2005).
  Article CAS PubMed Google Scholar
• Osuka, K., Feustel, P. J., Mongin, A. A., Tranmer, B. I. & Kimelberg, H. K. Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat. J. Neurochem. 76, 1842–1850 (2001). Suggests that tamoxifen is an inhibitor of Ca 2+ /calmodulin-dependent NOS and the subsequent peroxynitrite production in transient focal cerebral ischaemia, which might represent one mechanism for the neuroprotective effect of tamoxifen.
  Article CAS PubMed Google Scholar
• 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
• Williams, S. M. et al. Glial glutamate transporter expression patterns in brains from multiple mammalian species. Glia 49, 520–541 (2005).
  Article PubMed Google Scholar
• Serini, G. & Bussolino, F. Common cues in vascular and axon guidance. Physiology (Bethesda) 19, 348–354 (2004).
  CAS Google Scholar
• Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).
  Article CAS PubMed Google Scholar
• Tsang, M. C., Lo, A. C., Cheung, P. T., Chung, S. S. & Chung, S. K. Perinatal hypoxia-/ischemia-induced endothelin-1 mRNA in astrocyte-like and endothelial cells. Neuroreport 12, 2265–2270 (2001).
  Article CAS PubMed Google Scholar
• Ehrenreich, H. The astrocytic endothelin system: toward solving a mystery focus on 'distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca2+ signaling'. Am. J. Physiol. 277, C614–C615 (1999).
  Article CAS PubMed Google Scholar
• Acker, T., Beck, H. & Plate, K. H. Cell type specific expression of vascular endothelial growth factor and angiopoietin-1 and -2 suggests an important role of astrocytes in cerebellar vascularization. Mech. Dev. 108, 45–57 (2001).
  Article CAS PubMed Google Scholar
• West, H., Richardson, W. D. & Fruttiger, M. Stabilization of the retinal vascular network by reciprocal feedback between blood vessels and astrocytes. Development 132, 1855–1862 (2005).
  Article CAS PubMed Google Scholar
• Sun, Y. et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J. Clin. Invest. 111, 1843–1851 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, H., Vutskits, L., Pepper, M. S. & Kiss, J. Z. VEGF is a chemoattractant for FGF-2-stimulated neural progenitors. J. Cell Biol. 163, 1375–1384 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Kosacka, J. et al. Angiopoietin-1 promotes neurite outgrowth from dorsal root ganglion cells positive for Tie-2 receptor. Cell Tissue Res. 320, 11–19 (2005).
  Article CAS PubMed Google Scholar
• Ward, N. L., Putoczki, T., Mearow, K., Ivanco, T. L. & Dumont, D. J. Vascular-specific growth factor angiopoietin 1 is involved in the organization of neuronal processes. J. Comp. Neurol. 482, 244–256 (2005).
  Article CAS PubMed Google Scholar
• Danielyan, L. et al. The blockade of endothelin A receptor protects astrocytes against hypoxic injury: common effects of BQ-123 and erythropoietin on the rejuvenation of the astrocyte population. Eur. J. Cell Biol. 84, 567–579 (2005).
  Article CAS PubMed Google Scholar
• Fagan, S. C., Hess, D. C., Hohnadel, E. J., Pollock, D. M. & Ergul, A. Targets for vascular protection after acute ischemic stroke. Stroke 35, 2220–2225 (2004).
  Article CAS PubMed Google Scholar
• Ott, P. & Larsen, F. S. Blood–brain barrier permeability to ammonia in liver failure: a critical reappraisal. Neurochem. Int. 44, 185–198 (2004).
  Article CAS PubMed Google Scholar
• Takahashi, H., Koehler, R. C., Brusilow, S. W. & Traystman, R. J. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am. J. Physiol. 261, H825–H829 (1991).
  CAS PubMed Google Scholar
• Willard-Mack, C. L. et al. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 71, 589–599 (1996).
  Article CAS PubMed Google Scholar
• Suarez, I., Bodega, G. & Fernandez, B. Glutamine synthetase in brain: effect of ammonia. Neurochem. Int. 41, 123–142 (2002).
  Article CAS PubMed Google Scholar
• Butterworth, R. F. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab. Brain Dis. 17, 221–227 (2002).
  Article CAS PubMed Google Scholar
• Sugimoto, H., Koehler, R. C., Wilson, D. A., Brusilow, S. W. & Traystman, R. J. Methionine sulfoximine, a glutamine synthetase inhibitor, attenuates increased extracellular potassium activity during acute hyperammonemia. J. Cereb. Blood Flow Metab. 17, 44–49 (1997).
  Article CAS PubMed Google Scholar
• Rama Rao, K. V., Chen, M., Simard, J. M. & Norenberg, M. D. Increased aquaporin-4 expression in ammonia-treated cultured astrocytes. Neuroreport 14, 2379–2382 (2003).
  Article CAS PubMed Google Scholar
• Bender, A. S. & Norenberg, M. D. Effects of ammonia on L-glutamate uptake in cultured astrocytes. Neurochem. Res. 21, 567–573 (1996).
  Article CAS PubMed Google Scholar
• Norenberg, M. D., Huo, Z., Neary, J. T. & Roig-Cantesano, A. The glial glutamate transporter in hyperammonemia and hepatic encephalopathy: relation to energy metabolism and glutamatergic neurotransmission. Glia 21, 124–133 (1997).
  Article CAS PubMed Google Scholar
• Knecht, K., Michalak, A., Rose, C., Rothstein, J. D. & Butterworth, R. F. Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure. Neurosci. Lett. 229, 201–203 (1997).
  Article CAS PubMed Google Scholar
• Watanabe, A. et al. Glutamic acid and glutamine levels in serum and cerebrospinal fluid in hepatic encephalopathy. Biochem. Med. 32, 225–231 (1984).
  Article CAS PubMed Google Scholar
• Michalak, A., Rose, C., Butterworth, J. & Butterworth, R. F. Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure. Hepatology 24, 908–913 (1996).
  Article CAS PubMed Google Scholar
• Monfort, P., Munoz, M. D., ElAyadi, A., Kosenko, E. & Felipo, V. Effects of hyperammonemia and liver failure on glutamatergic neurotransmission. Metab. Brain Dis. 17, 237–250 (2002).
  Article CAS PubMed Google Scholar
• Rose, C., Kresse, W. & Kettenmann, H. Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J. Biol. Chem. 280, 20937–20944 (2005). Shows that hyperammonaemia produces an increase in [Ca 2+]i and triggers glial glutamate release in cultured astrocytes. This mechanism might contribute to disorders associated with glutamate-dependent overexcitation.
  Article CAS PubMed Google Scholar
• Szerb, J. C. & Butterworth, R. F. Effect of ammonium ions on synaptic transmission in the mammalian central nervous system. Prog. Neurobiol. 39, 135–153 (1992).
  Article CAS PubMed Google Scholar
• Michalak, A. & Butterworth, R. F. Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5-fluorowillardiine in the brains of rats with acute liver failure. Hepatology 25, 631–635 (1997).
  Article CAS PubMed Google Scholar
• Götz, M. Glial cells generate neurons — master control within CNS regions: developmental perspectives on neural stem cells. Neuroscientist 9, 379–397 (2003).
  Article CAS PubMed Google Scholar
• Eichmann, A., Makinen, T. & Alitalo, K. Neural guidance molecules regulate vascular remodeling and vessel navigation. Genes Dev. 19, 1013–1021 (2005).
  Article CAS PubMed Google Scholar
• Binder, D. K., Papadopoulos, M. C., Haggie, P. M. & Verkman, A. S. In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J. Neurosci. 24, 8049–8056 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Uckermann, O. et al. Glutamate-evoked alterations of glial and neuronal cell morphology in the guinea pig retina. J. Neurosci. 24, 10149–10158 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Izumi, Y. et al. Swelling of Müller cells induced by AP3 and glutamate transport substrates in rat retina. Glia 17, 285–293 (1996).
  Article CAS PubMed Google Scholar
• MacVicar, B. A., Feighan, D., Brown, A. & Ransom, B. Intrinsic optical signals in the rat optic nerve: role for K+ uptake via NKCC1 and swelling of astrocytes. Glia 37, 114–123 (2002).
  Article PubMed Google Scholar
• Strange, K. Cellular volume homeostasis. Adv. Physiol. Educ. 28, 155–159 (2004).
  Article PubMed Google Scholar
• Parkerson, K. A. & Sontheimer, H. Biophysical and pharmacological characterization of hypotonically activated chloride currents in cortical astrocytes. Glia 46, 419–436 (2004).
  Article PubMed PubMed Central Google Scholar
• Nielsen, S. et al. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neurosci. 17, 171–180 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Nagelhus, E. A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54 (1999).
  Article CAS PubMed Google Scholar
• Niermann, H., Amiry-Moghaddam, M., Holthoff, K., Witte, O. W. & Ottersen, O. P. A novel role of vasopressin in the brain: modulation of activity-dependent water flux in the neocortex. J. Neurosci. 21, 3045–3051 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Amiry-Moghaddam, M. et al. Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of α-syntrophin-null mice. Proc. Natl Acad. Sci. USA 100, 13615–13620 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Nagelhus, E. A., Mathiisen, T. M. & Ottersen, O. P. Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 129, 905–913 (2004).
  Article CAS PubMed Google Scholar
• Papadopoulos, M. C. & Verkman, A. S. Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J. Biol. Chem. 280, 13906–13912 (2005).
  Article CAS PubMed Google Scholar
• Bloch, O., Papadopoulos, M. C., Manley, G. T. & Verkman, A. S. Aquaporin-4 gene deletion in mice increases focal edema associated with staphylococcal brain abscess. J. Neurochem. 95, 254–262 (2005).
  Article CAS PubMed Google Scholar
• Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003).
  Article CAS PubMed PubMed Central Google Scholar