Key Points
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All malignant gliomas share an important feature: aggressive invasiveness. This invasion is largely contained within the cranium, typically without metastasis to other organs.
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Glioma cells secrete brevican and tenascins into the extracellular space, promoting migration. They also release proteases, including membrane type matrix metalloproteinase 1 (MMP1), MMP2 and MMP9, to degrade the dense extracellular matrix, which provides a path for migration.
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Bradykinin is produced in vascular endothelial cells and promotes the association of human glioma cells with blood vessels. Inhibition of bradykinin receptors on glioma cells with icatibant, a US Food and Drug Administration (FDA)-approved drug, significantly reduces glioma cell migration and association with blood vessels.
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Glioma cells undergo hydrodynamic shape and volume changes, changing volume by up to 33% to fit through the narrow extracellular spaces of the brain. Cell volume changes are accomplished by the efflux of salt though K+ and Cl− channels, leading to subsequent osmotic release of cytoplasmic water.
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The close association of glioma cells with the vasculature disrupts the interaction between astrocytic endfeet and endothelial cells. This in turn leads to a breakdown of the blood–brain barrier and abolishes the neurovascular unit where astrocytes locally regulate blood flow.
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Glutamate is released from glioma cells through system xc−. This glutamate acts in an autocrine and paracrine manner to promote glioma migration and proliferation, kills peritumoural neurons through excitotoxicity and increases neuronal excitability, leading to seizures. Sulfasalazine, an FDA-approved drug, inhibits glioma-induced seizures by blocking glutamate released through system xc−.
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Glioma cells use the same extracellular routes for migration as immature neurons, repurpose ion channels to undergo volume changes during migration and release excessive amounts of glutamate, culminating in seizures and neuronal death. Understanding this unique biology of gliomas through a neurocentric perspective reveals brain-specific therapeutic targets that have thus far not been exploited.
Abstract
Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood–brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease.
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References
Central Brain Tumor Registry of the United States. CBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States 2004–2006. CBTRUS [online], (2010).
Dandy, W. E. Removal of right cerebral hemisphere for certain tumors with hemiplegia: preliminary report. JAMA 90, 823–825 (1928).
Hou, L. C., Veeravagu, A., Hsu, A. R. & Tse, V. C. Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg. Focus 20, E5 (2006).
Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010). This paper shows that gliomas can be molecularly classified into four subtypes (pro-neural, neural, classical and mesenchymal) that respond differently to therapeutic intervention.
Huse, J. T. & Holland, E. C. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nature Rev. Cancer 10, 319–331 (2010).
Chen, J., McKay, R. M. & Parada, L. F. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149, 36–47 (2012).
Sanai, N., Alvarez-Buylla, A. & Berger, M. S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).
Stiles, C. D. & Rowitch, D. H. Glioma stem cells: a midterm exam. Neuron. 58, 832–846 (2008).
Zong, H., Verhaak, R. G. & Canoll, P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert. Rev. Mol. Diagn. 12, 383–394 (2012).
Sanai, N. et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478, 382–386 (2011).
Sugiarto, S. et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20, 328–340 (2011).
Liu, C. et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209–221 (2011).
Friedmann-Morvinski, D. et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338, 1080–1084 (2012).
Beauchesne, P. Extra-neural metastases of malignant gliomas: myth or reality? Cancers 3, 461–477 (2011).
Hamilton, J. D. et al. Glioblastoma multiforme metastasis outside the CNS: three case reports and possible mechanisms of escape. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2013.48.7546 (2014).
Lun, M., Lok, E., Gautam, S., Wu, E. & Wong, E. T. The natural history of extracranial metastasis from glioblastoma multiforme. J. Neurooncol. 105, 261–273 (2011).
Bernstein, J. J. & Woodard, C. A. Glioblastoma cells do not intravasate into blood vessels. Neurosurgery 36, 124–132 (1995).
Slowik, F. & Balogh, I. Extracranial spreading of glioblastoma multiforme. Zentralbl. Neurochir. 41, 57–68 (1980).
Gritsenko, P. G., Ilina, O. & Friedl, P. Interstitial guidance of cancer invasion. J. Pathol. 226, 185–199 (2012).
Zimmermann, D. R. & Dours-Zimmermann, M. T. Extracellular matrix of the central nervous system: from neglect to challenge. Histochem. Cell Biol. 130, 635–653 (2008).
Mentlein, R., Hattermann, K. & Held-Feindt, J. Lost in disruption: role of proteases in glioma invasion and progression. Biochim. Biophys. Acta 1825, 178–185 (2012).
Zhang, H., Kelly, G., Zerillo, C., Jaworski, D. M. & Hockfield, S. Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion in vivo. J. Neurosci. 18, 2370–2376 (1998).
Brosicke, N., van Landeghem, F. K., Scheffler, B. & Faissner, A. Tenascin-C is expressed by human glioma in vivo and shows a strong association with tumor blood vessels. Cell Tissue Res. 354, 409–430 (2013).
Joester, A. & Faissner, A. The structure and function of tenascins in the nervous system. Matrix Biol. 20, 13–22 (2001).
Martina, E. et al. Tenascin-W is a specific marker of glioma-associated blood vessels and stimulates angiogenesis in vitro. FASEB J. 24, 778–787 (2010).
Alves, T. R. et al. Tenascin-C in the extracellular matrix promotes the selection of highly proliferative and tubulogenesis-defective endothelial cells. Exp. Cell Res. 317, 2073–2085 (2011).
Sixt, M. et al. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J. Cell Biol. 153, 933–946 (2001).
Reese, T. S. & Karnovsky, M. J. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34, 207–217 (1967).
Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev. Cancer 3, 422–433 (2003).
Fukushima, Y., Tamura, M., Nakagawa, H. & Itoh, K. Induction of glioma cell migration by vitronectin in human serum and cerebrospinal fluid. J. Neurosurg. 107, 578–585 (2007).
Ohnishi, T. et al. Fibronectin-mediated cell migration promotes glioma cell invasion through chemokinetic activity. Clin. Exp. Metastasis 15, 538–546 (1997).
Persidsky, Y., Ramirez, S. H., Haorah, J. & Kanmogne, G. D. Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J. Neuroimmune Pharmacol. 1, 223–236 (2006).
Ridley, A. J. et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003).
Beadle, C. et al. The role of myosin II in glioma invasion of the brain. Mol. Biol. Cell 19, 3357–3368 (2008).
Wolfenson, H., Lavelin, I. & Geiger, B. Dynamic regulation of the structure and functions of integrin adhesions. Dev. Cell 24, 447–458 (2013).
Demuth, T. & Berens, M. E. Molecular mechanisms of glioma cell migration and invasion. J. Neurooncol. 70, 217–228 (2004).
Kwiatkowska, A. & Symons, M. Signaling determinants of glioma cell invasion. Adv. Exp. Med. Biol. 986, 121–141 (2013).
Lucio-Eterovic, A. K., Piao, Y. & de Groot, J. F. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin. Cancer Res. 15, 4589–4599 (2009).
Scaringi, C., Minniti, G., Caporello, P. & Enrici, R. M. Integrin inhibitor cilengitide for the treatment of glioblastoma: a brief overview of current clinical results. Anticancer Res. 32, 4213–4223 (2012).
Reardon, D. A. et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol. 26, 5610–5617 (2008).
Montana, V. & Sontheimer, H. Bradykinin promotes the chemotactic invasion of primary brain tumors. J. Neurosci. 31, 4858–4867 (2011). In this paper, bradykinin is shown to bind to the B2R on glioma cells, attracting the majority of glioma cells to blood vessels and increasing migration.
Kang, S. S. et al. Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival. Cancer Res. 70, 1173–1183 (2010).
Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).
Thorne, R. G. & Nicholson, C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc. Natl Acad. Sci. USA 103, 5567–5572 (2006).
Farin, A. et al. Transplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia 53, 799–808 (2006).
Watkins, S. & Sontheimer, H. Hydrodynamic cellular volume changes enable glioma cell invasion. J. Neurosci. 31, 17250–17259 (2011). This study shows that the cellular volume of human glioma cells migrating through cerebral parenchyma oscillates by 33%, enabling these cells to fit through narrow spaces in the brain.
McCoy, E. & Sontheimer, H. Expression and function of water channels (Aquaporins) in migrating malignant astrocytes. Glia 55, 1034–1043 (2007).
Ding, T. et al. Role of aquaporin-4 in the regulation of migration and invasion of human glioma cells. Int. J. Oncol. 38, 1521–1531 (2011).
McCoy, E. S., Haas, B. R. & Sontheimer, H. Water permeability through aquaporin-4 is regulated by protein kinase C and becomes rate-limiting for glioma invasion. Neuroscience 168, 971–981 (2009).
Cuddapah, V. A., Turner, K. L., Seifert, S. & Sontheimer, H. Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. J. Neurosci. 33, 1427–1440 (2013). A study showing that bradykinin promotes migration by activating ion channels that are involved in volume regulation in glioma cells.
Habela, C. W., Ernest, N. J., Swindall, A. F. & Sontheimer, H. Chloride accumulation drives volume dynamics underlying cell proliferation and migration. J. Neurophysiol. 101, 750–757 (2009).
Garzon-Muvdi, T. et al. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. PLoS Biol. 10, e1001320 (2012).
Haas, B. R. et al. With-No-Lysine Kinase 3 (WNK3) stimulates glioma invasion by regulating cell volume. Am. J. Physiol. Cell Physiol. 301, C1150–C1160 (2011).
Haas, B. R. & Sontheimer, H. Inhibition of the sodium-potassium-chloride cotransporter isoform-1 reduces glioma invasion. Cancer Res. 70, 5597–5606 (2010).
Cuddapah, V. A. & Sontheimer, H. Molecular interaction and functional regulation of ClC-3 by Ca2+/calmodulin-dependent protein kinase II (CaMKII) in human malignant glioma. J. Biol. Chem. 285, 11188–11196 (2010).
Soroceanu, L., Manning, T. J. Jr & Sontheimer, H. Modulation of glioma cell migration and invasion using Cl− and K+ ion channel blockers. J. Neurosci. 19, 5942–5954 (1999). This study introduces a hydrodynamic model of cell invasion and shows that K+ and Cl− channels promote glioma cell invasion.
Lui, V. C., Lung, S. S., Pu, J. K., Hung, K. N. & Leung, G. K. Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3. Anticancer Res. 30, 4515–4524 (2010).
Soroceanu, L., Gillespie, Y., Khazaeli, M. B. & Sontheimer, H. Use of chlorotoxin for targeting of primary brain tumors. Cancer Res. 58, 4871–4879 (1998).
Mamelak, A. N. et al. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J. Clin. Oncol. 24, 3644–3650 (2006). This Phase I trial is the first to demonstrate that a Cl− channel inhibitor (chlorotoxin) specifically binds to gliomas in patients.
Hockaday, D. C. et al. Imaging glioma extent with 131I-TM-601. J. Nucl. Med. 46, 580–586 (2005).
Veiseh, M. et al. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res. 67, 6882–6888 (2007).
Weaver, A. K., Bomben, V. C. & Sontheimer, H. Expression and function of calcium-activated potassium channels in human glioma cells. Glia. 54, 223–233 (2006).
McFerrin, M. B., Turner, K. L., Cuddapah, V. A. & Sontheimer, H. Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death. Am. J. Physiol. Cell Physiol. 303, C1070–C1078 (2012).
D'Alessandro, G. et al. KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death Dis. 4, e773 (2013).
Sciaccaluga, M. et al. CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am. J. Physiol. Cell Physiol. 299, C175–C184 (2010).
Ransom, C. B. & Sontheimer, H. B. K. Channels in human glioma cells. J. Neurophysiol. 85, 790–803 (2001).
Ransom, C. B., Liu, X. & Sontheimer, H. BK channels in human glioma cells have enhanced calcium sensitivity. Glia 38, 281–291 (2002).
Liu, X., Chang, Y., Reinhart, P. H., Sontheimer, H. & Chang, Y. Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells. J. Neurosci. 22, 1840–1849 (2002).
Manning, T. J. Jr, Parker, J. C. & Sontheimer, H. Role of lysophosphatidic acid and Rho in glioma cell motility. Cell. Motil. Cytoskeleton 45, 185–199 (2000).
Wen, P. Y. & Kesari, S. Malignant gliomas in adults. N. Engl. J. Med. 359, 492–507 (2008).
Bomben, V. C., Turner, K. L., Barclay, T. T. & Sontheimer, H. Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas. J. Cell. Physiol. 226, 1879–1888 (2011).
Cuddapah, V. A., Turner, K. L. & Sontheimer, H. Calcium entry via TRPC1 channels activates chloride currents in human glioma cells. Cell Calcium 53, 187–194 (2013).
Caric, D. et al. EGFRs mediate chemotactic migration in the developing telencephalon. Development 128, 4203–4216 (2001).
Lindberg, O. R., Persson, A., Brederlau, A., Shabro, A. & Kuhn, H. G. EGF-induced expansion of migratory cells in the rostral migratory stream. PLoS ONE 7, e46380 (2012).
Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nature Neurosci. 10, 1369–1376 (2007).
Mathiisen, T. M., Lehre, K. P., Danbolt, N. C. & Ottersen, O. P. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58, 1094–1103 (2010).
Yousif, L. F., Di Russo, J. & Sorokin, L. Laminin isoforms in endothelial and perivascular basement membranes. Cell Adh. Migr. 7, 101–110 (2013).
Wolburg, H., Noell, S., Mack, A., Wolburg-Buchholz, K. & Fallier-Becker, P. Brain endothelial cells and the glio-vascular complex. Cell Tissue Res. 335, 75–96 (2009).
Wolburg, H., Noell, S., Wolburg-Buchholz, K., Mack, A. & Fallier-Becker, P. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier. Neuroscientist 15, 180–193 (2009).
Nagelhus, E. A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54 (1999).
Magistretti, P. J., Pellerin, L., Rothman, D. L. & Shulman, R. G. Energy on demand. Science 283, 496–497 (1999).
Watkins, S. et al. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nature Commun. (in the press). This recent study demonstrates that invading glioma cells disrupt physiological interactions between astrocytes and blood vessels, hijack control of vascular tone and break down the BBB.
Zagzag, D. et al. Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab. Invest. 80, 837–849 (2000).
Nagano, N., Sasaki, H., Aoyagi, M. & Hirakawa, K. Invasion of experimental rat brain tumor: early morphological changes following microinjection of C6 glioma cells. Acta Neuropathol. 86, 117–125 (1993).
Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).
de Groot, J. & Sontheimer, H. Glutamate and the biology of gliomas. Glia 59, 1181–1189 (2010).
Ye, Z. C. & Sontheimer, H. Glioma cells release excitotoxic concentrations of glutamate. Cancer Res. 59, 4383–4391 (1999). This study is the first to show that inhibition of glutamate release from glioma cells (and thus of the resulting glutamate excitotoxicity) decreases neurotoxicity.
Lyons, S. A., Chung, W. J., Weaver, A. K., Ogunrinu, T. & Sontheimer, H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res. 67, 9463–9471 (2007).
Ishiuchi, S. et al. Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nature Med. 8, 971–978 (2002). This study shows that glutamate acts at Ca2+-permeable AMPA receptors in glioma cells to promote migration.
Marcus, H. J., Carpenter, K. L., Price, S. J. & Hutchinson, P. J. In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J. Neurooncol. 97, 11–23 (2010).
Takeuchi, S. et al. Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. Neurosurgery 72, 33–41 (2013).
Chung, W. J. et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J. Neurosci. 25, 7101–7110 (2005).
Buckingham, S. C. et al. Glutamate release by primary brain tumors induces epileptic activity. Nature Med. 17, 1269–1274 (2011). A study showing that gliomas release glutamate through system x c−. This leads to epileptic activity, which can be inhibited by sulfasalazine, an FDA-approved drug.
Campbell, S. L., Buckingham, S. C. & Sontheimer, H. Human glioma cells induce hyperexcitability in cortical networks. Epilepsia 53, 1360–1370 (2012).
Ishiuchi, S. et al. Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J. Neurosci. 27, 7987–8001 (2007).
Chung, W. J. & Sontheimer, H. Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-κB. J. Neurochem. 110, 182–193 (2009).
Robe, P. A. et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer 9, 372 (2009).
Scherer, H. J. Structural development in gliomas. Am. J. Cancer 34, 333–351 (1938). This visionary description by Scherer demonstrates the most common sites for glioma invasion, now known as Scherer's structures.
Bozoyan, L., Khlghatyan, J. & Saghatelyan, A. Astrocytes control the development of the migration-promoting vasculature scaffold in the postnatal brain via VEGF signaling. J. Neurosci. 32, 1687–1704 (2012).
Saghatelyan, A. Role of blood vessels in the neuronal migration. Semin. Cell Dev. Biol. 20, 744–750 (2009).
Bardehle, S. et al. Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nature Neurosci. 16, 580–586 (2013).
Hughes, E. G., Kang, S. H., Fukaya, M. & Bergles, D. E. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nature Neurosci. 16, 668–676 (2013).
Jablonska, B. et al. Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nature Neurosci. 13, 541–550 (2010).
Cayre, M., Canoll, P. & Goldman, J. E. Cell migration in the normal and pathological postnatal mammalian brain. Prog. Neurobiol. 88, 41–63 (2009).
Komuro, H. & Rakic, P. Intracellular Ca2+ fluctuations modulate the rate of neuronal migration. Neuron 17, 275–285 (1996).
Turner, K. L. & Sontheimer, H. KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb. Cortex http://dx.doi.org/10.1093/cercor/bht090 (2013).
Scherer, H. J. A critical review: the pathology of cerebral gliomas. J. Neurol. Psychiatry 3, 147–177 (1940).
Meighan, S. E. et al. Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J.Neurochem. 96, 1227–1241 (2006).
Bovetti, S., Bovolin, P., Perroteau, I. & Puche, A. C. Subventricular zone-derived neuroblast migration to the olfactory bulb is modulated by matrix remodelling. Eur. J. Neurosci. 25, 2021–2033 (2007).
Clegg, D. O., Wingerd, K. L., Hikita, S. T. & Tolhurst, E. C. Integrins in the development, function and dysfunction of the nervous system. Front. Biosci. 8, d723–d750 (2003).
Venero, J. L., Vizuete, M. L., Machado, A. & Cano, J. Aquaporins in the central nervous system. Prog. Neurobiol. 63, 321–336 (2001).
Farmer, L. M., Le, B. N. & Nelson, D. J. CLC-3 chloride channels moderate long-term potentiation at Schaffer collateral-CA1 synapses. J. Physiol. 591, 1001–1015 (2013).
Riazanski, V. et al. Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus. Nature Neurosci. 14, 487–494 (2011).
Du, W. et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nature Genet. 37, 733–738 (2005).
Brenner, R. et al. BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nature Neurosci. 8, 1752–1759 (2005).
Yamada, J. et al. Cl− uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1. J. Physiol. 557, 829–841 (2004).
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).
McBean, G. J. Cerebral cystine uptake: a tale of two transporters. Trends Pharmacol. Sci. 23, 299–302 (2002).
Acknowledgements
This work was supported by US National Institutes of Health (NIH) research grants 2RO1-NS036692, 5RO1NS031234, 1RO1-NS082851 and 5RO1-NS052634 to H.S., V.A.C. (F31NS073181) and S.W. (F31NS074597) were supported by Ruth L. Kirschstein National Research Service Awards. S.R. received funding from the German Research Foundation (DFG), the Epilepsy Foundation and the American Brain Tumor Association (ABTA).
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Cuddapah, V., Robel, S., Watkins, S. et al. A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15, 455–465 (2014). https://doi.org/10.1038/nrn3765
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