GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy: Reduced KCC2 Underlie Tumor-Related Epilepsy
Open accessAbstract
Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl(-) concentration ([Cl(-) ]i ) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl(-) ]i required for GABAA R-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cellular and molecular changes underlying tumor-associated epilepsy collectively point to a decrease in GABAergic and increase in glutamatergic transmission as the major contributors.
“The cellular and molecular changes underlying tumor-associated epilepsy collectively point to a decrease in GABAergic and increase in glutamatergic transmission as the major contributors3–6.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
The peritumoral brain shows approximately 35% reduction in the density of fast spiking GABAergic interneurons.
“the peritumoral brain shows ~35% reduction in the density of fast spiking GABAergic interneurons3”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
The remaining GABAergic neurons in peritumoral brain show a significantly reduced inhibitory potential.
“the remaining GABAergic neurons show a significantly reduced inhibitory potential.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
Glutamate release is necessary but insufficient to drive peritumoral epilepsy; an additional loss of GABAergic inhibition is required.
“Glu release, while necessary, is insufficient to drive peritumoral epilepsy3. Rather an additional loss of GABAergic inhibition is required”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
Seizures originate from the PTC, and previous studies show altered excitation−inhibition balance in the PTC due to changes in glutamatergic and GABAergic activity.
“Seizures originate from the PTC, and previous studies3,5,6 show altered excitation−inhibition balance in the PTC due to changes in glutamatergic and GABAergic activity.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [3]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
Danbolt, N. C. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00067-8 · Cited by 4,068 · see citing works
Excitatory actions of gaba during development: the nature of the nurture
Ben-Ari, Y. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn920 · Cited by 2,448 · see citing works
Glioblastoma and Other Malignant Gliomas
Omuro, A. M. P. (2013) · JAMA · doi:10.1001/jama.2013.280319 · Cited by 2,308 · see citing works
The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation
Rivera, C., Voipio, J., Payne, J. A., Ruusuvuori, E., Lahtinen, H., Lamsa, K., Pirvola, U., Saarma, M., & Kaila, K. (1999) · Nature · doi:10.1038/16697 · Cited by 2,152 · see citing works
Incidence of Epilepsy and Unprovoked Seizures in Rochester, Minnesota: 1935–1984
Hauser, W. A., Annegers, J. F., & Kurland, L. T. (1993) · Epilepsia · doi:10.1111/j.1528-1157.1993.tb02586.x · Cited by 2,084 · see citing works
GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations
Ben-Ari, Y., Gaiarsa, J.-L., Tyzio, R., & Khazipov, R. (2007) · Physiological Reviews · doi:10.1152/physrev.00017.2006 · Cited by 1,304 · see citing works
GABA: an excitatory transmitter in early postnatal life
Cherubini, E., Gaïarsa, J., & Ben‐Ari, Y. (1991) · Trends in Neurosciences · doi:10.1016/0166-2236(91)90003-d · Cited by 1,108 · see citing works
On the Origin of Interictal Activity in Human Temporal Lobe Epilepsy in Vitro
Cohen, I., Navarro, V., Clémenceau, S., Baulac, M., & Miles, R. (2002) · Science · doi:10.1126/science.1076510 · Cited by 1,001 · see citing works
The GABA Excitatory/Inhibitory Shift in Brain Maturation and Neurological Disorders
Ben‐Ari, Y., Khalilov, I., Kahle, K. T., & Cherubini, E. (2012) · The Neuroscientist · doi:10.1177/1073858412438697 · Cited by 622 · see citing works
Self-citationGlutamate release promotes growth of malignant gliomas
Takano, T., Lin, J. H.-C., Arcuino, G., Gao, Q., Yang, J., & Nedergaard, M. (2001) · Nature Medicine · doi:10.1038/nm0901-1010 · Cited by 602 · see citing works
Glutamate release by primary brain tumors induces epileptic activity
Buckingham, S. C., Campbell, S. L., Haas, B. R., Montana, V., Robel, S., Ogunrinu, T., & Sontheimer, H. (2011) · Nature Medicine · doi:10.1038/nm.2453 · Cited by 578 · see citing works
Self-citationMolecular Characterization of a Putative K-Cl Cotransporter in Rat Brain
Payne, J. A., Stevenson, T. J., & Donaldson, L. F. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.27.16245 · Cited by 568 · see citing works
Seizure characteristics and control following resection in 332 patients with low-grade gliomas
Chang, E. F., Potts, M. B., Keles, G. E., Lamborn, K. R., Chang, S. M., Barbaro, N. M., & Berger, M. S. (2008) · Journal of neurosurgery · doi:10.3171/jns/2008/108/2/0227 · Cited by 528 · see citing works
Scharfman, H. E. (2007) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-007-0053-z · Cited by 524 · see citing works
Glioma cells release excitotoxic concentrations of glutamate.
Ye, Z., & Sontheimer, H. W. (1999) · PubMed · Cited by 442 · see citing works
Self-citationRoles of the cation–chloride cotransporters in neurological disease
Kahle, K. T., Staley, K. J., Nahed, B. V., Gamba, G., Hébert, S., Lifton, R. P., & Mount, D. B. (2008) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0883 · Cited by 407 · see citing works
Self-citationWang, Y. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.4.395 · Cited by 371 · see citing works
Ye, Z., Rothstein, J. D., & Sontheimer, H. W. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-24-10767.1999 · Cited by 353 · see citing works
Self-citationPorter, K. R., McCarthy, B. J., Freels, S. A., Kim, Y., & Davis, F. (2010) · Neuro-Oncology · doi:10.1093/neuonc/nop066 · Cited by 346 · see citing works
Giannini, C., Sarkaria, J. N., Saito, A., Uhm, J. H., Galanis, E., Carlson, B. L., Schroeder, M. A., & James, C. D. (2005) · Neuro-Oncology · doi:10.1215/s1152851704000821 · Cited by 326 · see citing works
Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors
Chung, W. J., Lyons, S. A., Nelson, G. M., Hamza, H., Gladson, C. L., Gillespie, G. Y., & Sontheimer, H. W. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.5258-04.2005 · Cited by 316 · see citing works
Self-citationNMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor–mediated currents
Lee, H. H. C., Deeb, T. Z., Walker, J., Davies, P. A., & Moss, S. J. (2011) · Nature Neuroscience · doi:10.1038/nn.2806 · Cited by 303 · see citing works
Glutamate and the biology of gliomas
de Groot, J., & Sontheimer, H. W. (2010) · Glia · doi:10.1002/glia.21113 · Cited by 290 · see citing works
Self-citationCalcium‐binding proteins as markers for subpopulations of GABAergic neurons in monkey striate cortex
van Brederode, J. F. M., Mulligan, K. A., & Hendrickson, A. E. (1990) · The Journal of Comparative Neurology · doi:10.1002/cne.902980102 · Cited by 284 · see citing works
Phosphoregulation of the Na–K–2Cl and K–Cl cotransporters by the WNK kinases
Kahle, K. T., Rinehart, J., & Lifton, R. P. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.07.009 · Cited by 203 · see citing works
Self-citationEpileptic seizures during follow-up of patients treated for primary brain tumors
Hildebrand, J. G., Lecaille, C., Perennes, J., & Delattre, J. (2005) · Neurology · doi:10.1212/01.wnl.0000168903.09277.8f · Cited by 197 · see citing works
Savaskan, N. E., Heckel, A., Hahnen, E., Engelhorn, T., Doerfler, A., Ganslandt, O., Nimsky, C., Buchfelder, M., & Eyüpoglu, I. Y. (2008) · Nature Medicine · doi:10.1038/nm1772 · Cited by 192 · see citing works
Marcus, H. J., Carpenter, K. L. H., Price, S. J., & Hutchinson, P. J. (2009) · Journal of Neuro-Oncology · doi:10.1007/s11060-009-9990-5 · Cited by 184 · see citing works
Ictal Epileptiform Activity Is Facilitated by Hippocampal GABAA Receptor-Mediated Oscillations
Köhling, R., Vreugdenhil, M., Bracci, E., & Jefferys, J. G. R. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-18-06820.2000 · Cited by 179 · see citing works
Glutamate is associated with a higher risk of seizures in patients with gliomas
Yuen, T., Morokoff, A. P., Bjorksten, A. R., D’Abaco, G. M., Paradiso, L., Finch, S. J., Wong, D., Reid, C. A., Powell, K. L., Drummond, K. J., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e318266fa89 · Cited by 173 · see citing works
Schwaller, B., Tetko, I. V., Tandon, P., Silveira, D. C., Vreugdenhil, M., Henzi, T., Potier, M.-C., Celio, M. R., & Villa, A. E. P. (2004) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2003.12.006 · Cited by 169 · see citing works
Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment
de Groot, M., Reijneveld, J. C., Aronica, E., & Heimans, J. J. (2011) · Brain · doi:10.1093/brain/awr310 · Cited by 163 · see citing works
Human glioma cells induce hyperexcitability in cortical networks
Campbell, S. L., Buckingham, S. C., & Sontheimer, H. W. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03557.x · Cited by 161 · see citing works
Self-citationCircuitry, Architecture, and Functional Dynamics of Visual Cortex
Gilbert, C. D. (1993) · Cerebral Cortex · doi:10.1093/cercor/3.5.373 · Cited by 158 · see citing works
Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus.
Andrioli, A., Alonso-Nanclares, L., Arellano, J. I., & DeFelipe, J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.07.029 · Cited by 147 · see citing works
Lee, H., Chen, C. X., Liu, Y., Aizenman, E., & Kandler, K. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04084.x · Cited by 137 · see citing works
Conti, L., Palma, E., Roseti, C., Lauro, C., Cipriani, R., de Groot, M., Aronica, E., & Limatola, C. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03111.x · Cited by 121 · see citing works
Stamatakis, E., Chau, J. Y., Pedišić, Ž., Bauman, A. E., Macniven, R., Coombs, N. A., & Hamer, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073753 · Cited by 119 · see citing works
Barmashenko, G., Hefft, S., Aertsen, A., Kirschstein, T., & Köhling, R. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03247.x · Cited by 110 · see citing works
Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy
Knopp, A., Frahm, C., Fidzinski, P., Witte, O. W., & Behr, J. (2008) · Brain · doi:10.1093/brain/awn095 · Cited by 110 · see citing works
NKCC1 and KCC2 prevent hyperexcitability in the mouse hippocampus
Zhu, L., Polley, N., Mathews, G. C., & Delpire, E. J. (2008) · Epilepsy Research · doi:10.1016/j.eplepsyres.2008.02.005 · Cited by 104 · see citing works
Ritz, M., & Hausmann, O. N. (2008) · Brain Research · doi:10.1016/j.brainres.2008.01.091 · Cited by 83 · see citing works
Isokawa, M. (1996) · Journal of Neurophysiology · doi:10.1152/jn.1996.75.5.1901 · Cited by 80 · see citing works
Smits, A., Jin, Z., Elsir, T., Pedder, H., Nistér, M., Alafuzoff, I. I., Dimberg, A., Edqvist, P.-H. D., Pontén, F., Aronica, E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037041 · Cited by 69 · see citing works
Drexel, M., Preidt, A. P., Kirchmair, E., & Sperk, G. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.05.021 · Cited by 66 · see citing works
With-No-Lysine Kinase 3 (WNK3) stimulates glioma invasion by regulating cell volume
Haas, B. R., Cuddapah, V. A., Watkins, S., Rohn‐Glowacki, K. J., Dy, T. E., & Sontheimer, H. W. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00203.2011 · Cited by 66 · see citing works
Self-citationCurrent status of therapy of solid tumors: brain tumor therapy.
Zalutsky, M. R. (2005) · PubMed · Cited by 61 · see citing works
A new form of feedback at the GABAA receptor
Staley, K. J., & Smith, R. L. (2001) · Nature Neuroscience · doi:10.1038/89439 · Cited by 39 · see citing works
Ratté, S., & Lacaille, J. (2006) · PubMed · Cited by 30 · see citing works
Multiple Protein Biomarker Assessment for Recombinant Bovine Somatotropin (rbST) Abuse in Cattle
Ludwig, S. K. J., Smits, N. G. E., van der Veer, G., Bremer, M. G. E. G., & Nielen, M. W. F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0052917 · Cited by 28 · see citing works
Cellular Mechanisms of Pharmacoresistance in Slices from Epilepsy Surgery
Deisz, R. A. (2002) · Novartis Foundation symposium · doi:10.1002/0470846356.ch14 · Cited by 21 · see citing works
Gramatzki, D., Herrmann, C., Hertler, C., Becker, K. A., Gulbins, E., Weller, M., & Tabatabai, G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063527 · Cited by 19 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [32]Lee HH Deeb TZ Walker JA Davies PA Moss SJ 2011b NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents Nat Neurosci 14 736 743 21532577 PMC3102766
Cited by
Sorted by citations
Electrical and synaptic integration of glioma into neural circuits
Venkatesh, H. S., Morishita, W., Geraghty, A. C., Silverbush, D., Gillespie, S. M., Arzt, M., Tam, L. T., Espenel, C., Ponnuswami, A., Ni, L., et al. (2019) · Nature · doi:10.1038/s41586-019-1563-y · Cited by 1,366 · see citing works
Cancer neuroscience: State of the field, emerging directions
Winkler, F., Venkatesh, H. S., Amit, M., Batchelor, T. T., Demir, İ. E., Deneen, B., Gutmann, D. H., Hervey‐Jumper, S. L., Kuner, T., Mabbott, D., et al. (2023) · Cell · doi:10.1016/j.cell.2023.02.002 · Cited by 578 · see citing works
Identification of diverse astrocyte populations and their malignant analogs
John Lin, C.-C., Yu, K., Hatcher, A., Huang, T.-W., Lee, H. K., Carlson, J., Weston, M. C., Chen, F., Zhang, Y., Zhu, W., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4493 · Cited by 525 · see citing works
Neuron–glia interactions in the pathophysiology of epilepsy
Patel, D. C., Tewari, B. P., Chaunsali, L., & Sontheimer, H. W. (2019) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0126-4 · Cited by 461 · see citing works
Self-citationGlioblastoma remodelling of human neural circuits decreases survival
Krishna, S., Choudhury, A., Keough, M. B., Seo, K., Ni, L., Kakaizada, S., Lee, A. J., Aabedi, A. A., Popova, G., Lipkin, B., et al. (2023) · Nature · doi:10.1038/s41586-023-06036-1 · Cited by 442 · see citing works
Mancusi, R. A., & Monje, M. (2023) · Nature · doi:10.1038/s41586-023-05968-y · Cited by 370 · see citing works
Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer
Petralia, F., Tignor, N., Reva, B., Koptyra, M., Chowdhury, S., Rykunov, D., Krek, A., Ma, W., Zhu, Y., Ji, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.044 · Cited by 317 · see citing works
Revisiting the role of neurotransmitters in epilepsy: An updated review.
Akyuz, E., Polat, A., Eroğlu, E., Kullu, I., Angelopoulou, E., & Paudel, Y. (2020) · Life Science · doi:10.1016/j.lfs.2020.118826 · Cited by 269 · see citing works
Reactive Astrogliosis Causes the Development of Spontaneous Seizures
Robel, S., Buckingham, S. C., Boni, J. L., Campbell, S. L., Danbolt, N. C., Riedemann, T., Sutor, B., & Sontheimer, H. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1574-14.2015 · Cited by 283 · see citing works
Self-citationPIK3CA variants selectively initiate brain hyperactivity during gliomagenesis
Yu, K., Lin, C.-C. J., Hatcher, A., Lozzi, B., Kong, K., Huang-Hobbs, E., Cheng, Y.-T., Beechar, V. B., Zhu, W., Zhang, Y., et al. (2020) · Nature · doi:10.1038/s41586-020-1952-2 · Cited by 256 · see citing works
WNK Kinase Signaling in Ion Homeostasis and Human Disease
Shekarabi, M., Zhang, J., Khanna, A. R., Ellison, D. H., Delpire, E. J., & Kahle, K. T. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.01.007 · Cited by 241 · see citing works
Self-citationTewari, B. P., Chaunsali, L., Campbell, S. L., Patel, D. C., Goode, A. E., & Sontheimer, H. (2018) · Nature Communications · doi:10.1038/s41467-018-07113-0 · Cited by 208 · see citing works
Self-citationSeizures and gliomas — towards a single therapeutic approach
Huberfeld, G., & Vecht, C. J. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.26 · Cited by 204 · see citing works
Glia as drivers of abnormal neuronal activity
Robel, S., & Sontheimer, H. W. (2015) · Nature Neuroscience · doi:10.1038/nn.4184 · Cited by 199 · see citing works
Self-citationGABAergic neuron-to-glioma synapses in diffuse midline gliomas
Barron, T., Yalçın, B., Su, M., Byun, Y. G., Gavish, A., Shamardani, K., Xu, H., Ni, L., Soni, N., Mehta, V., et al. (2025) · Nature · doi:10.1038/s41586-024-08579-3 · Cited by 165 · see citing works
Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities
Shi, D. D., Guo, J. A., Hoffman, H. I., Su, J., Mino-Kenudson, M. A., Barth, J. L., Schenkel, J. M., Loeffler, J. S., Shih, H. A., Hong, T. S., et al. (2022) · The Lancet Oncology · doi:10.1016/s1470-2045(21)00596-9 · Cited by 146 · see citing works
Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing
Tetzlaff, S. K., Reyhan, E., Layer, N., Bengtson, C. P., Heuer, A., Schroers, J., Faymonville, A. J., Langeroudi, A. P., Drewa, N., Keifert, E., et al. (2024) · Cell · doi:10.1016/j.cell.2024.11.002 · Cited by 147 · see citing works
Seizing Control of KCC2: A New Therapeutic Target for Epilepsy
Moore, Y. E., Kelley, M. R., Brandon, N. J., Deeb, T. Z., & Moss, S. J. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.06.008 · Cited by 142 · see citing works
Emerging intersections between neuroscience and glioma biology
Jung, E., Alfonso, J., Osswald, M., Monyer, H., Wick, W., & Winkler, F. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0540-y · Cited by 139 · see citing works
Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures
Moore, Y. E., Deeb, T. Z., Chadchankar, H., Brandon, N. J., & Moss, S. J. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1810134115 · Cited by 122 · see citing works
A prognostic neural epigenetic signature in high-grade glioma
Drexler, R., Khatri, R., Sauvigny, T., Mohme, M., Maire, C. L., Ryba, A. S., Zghaibeh, Y., Dührsen, L., Salviano‐Silva, A., Lamszus, K., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02969-w · Cited by 122 · see citing works
Tumor-related epilepsy: epidemiology, pathogenesis and management
Chen, D. Y., Chen, C. C., Crawford, J. R., & Wang, S. G. (2018) · Journal of Neuro-Oncology · doi:10.1007/s11060-018-2862-0 · Cited by 116 · see citing works
GABA ergic signalling in the immune system
Barragán, A., Weidner, J. M., Jin, Z., Korpi, E. R., & Birnir, B. (2015) · Acta Physiologica · doi:10.1111/apha.12467 · Cited by 111 · see citing works
Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma model
Hatcher, A., Yu, K., Meyer, J. F., Aiba, I., Deneen, B., & Noebels, J. L. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133316 · Cited by 107 · see citing works
Montgomery, M. K., Kim, S. H., Dovas, A., Zhao, H., Goldberg, A., Xu, W., Yagielski, A. J., Cambareri, M. K., Patel, K., Mela, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.064 · Cited by 104 · see citing works
Neuron–oligodendroglial interactions in health and malignant disease
Taylor, K. R., & Monje, M. (2023) · Nature reviews. Neuroscience · doi:10.1038/s41583-023-00744-3 · Cited by 101 · see citing works
Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment
Radin, D. P., & Tsirka, S. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228476 · Cited by 99 · see citing works
van Hugte, E., Schubert, D., & Kasri, N. N. (2023) · Epilepsia · doi:10.1111/epi.17651 · Cited by 94 · see citing works
Anastasaki, C., Mo, J., Chen, J., Chatterjee, J., Pan, Y., Scheaffer, S. M., Cobb, O. M., Monje, M., Le, L. Q., & Gutmann, D. H. (2022) · Nature Communications · doi:10.1038/s41467-022-30466-6 · Cited by 93 · see citing works
KCC2 downregulation facilitates epileptic seizures
Chen, L., Wan, L., Wu, Z., Ren, W., Huang, Y., Qian, B., & Wang, Y. (2017) · Scientific Reports · doi:10.1038/s41598-017-00196-7 · Cited by 86 · see citing works
Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation
Curry, R. N., Aiba, I., Meyer, J. F., Lozzi, B., Ko, Y., McDonald, M. F., Rosenbaum, A., Cervantes, A., Huang-Hobbs, E., Cocito, C., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.01.013 · Cited by 84 · see citing works
Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment
McMoneagle, E., Zhou, J. Q., Zhang, S., Huang, W., Josiah, S. S., Ding, K., Wang, Y., & Zhang, J. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01149-9 · Cited by 78 · see citing works
Diffuse Low-Grade Glioma-Related Epilepsy
Pallud, J., & McKhann, G. M. (2018) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2018.09.001 · Cited by 74 · see citing works
Roles of glial ion transporters in brain diseases
Song, S., Luo, L., Sun, B., & Sun, D. (2019) · Glia · doi:10.1002/glia.23699 · Cited by 72 · see citing works
Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling
Drexler, R., Drinnenberg, A., Gavish, A., Yalçın, B., Shamardani, K., Rogers, A. E., Mancusi, R. A., Trivedi, V. S., Taylor, K. R., Kim, Y. S., et al. (2025) · Cell · doi:10.1016/j.cell.2025.05.031 · Cited by 76 · see citing works
Compromised GABAergic inhibition contributes to tumor-associated epilepsy
MacKenzie, G., O’Toole, K. K., Moss, S. J., & Maguire, J. L. (2016) · Epilepsy Research · doi:10.1016/j.eplepsyres.2016.07.010 · Cited by 70 · see citing works
The KCC2 Cotransporter and Human Epilepsy
Kahle, K. T., Khanna, A. R., Duan, J., Staley, K. J., Delpire, E. J., & Poduri, A. (2016) · The Neuroscientist · doi:10.1177/1073858416645087 · Cited by 69 · see citing works
Self-citationJung, E., Alfonso, J., Monyer, H., Wick, W., & Winkler, F. (2020) · International Journal of Cancer · doi:10.1002/ijc.33138 · Cited by 66 · see citing works
Seizures in glioma patients: An overview of incidence, etiology, and therapies
Samudra, N. P., Zacharias, T., Plitt, A. R., Lega, B. C., & Pan, E. (2019) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2019.07.026 · Cited by 59 · see citing works
Glioma-neuronal circuit remodeling induces regional immunosuppression
Nejo, T., Krishna, S., Yamamichi, A., Lakshmanachetty, S., Jimenez, C., Lee, K. Y., Baker, D. L., Young, J. S., Chen, T., Phyu, S. M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60074-z · Cited by 58 · see citing works
Ye, H., & Kaszuba, S. V. (2017) · Journal of Biomedical Science · doi:10.1186/s12929-017-0399-8 · Cited by 56 · see citing works
Tantillo, E., Vannini, E., Cerri, C., Spalletti, C., Colistra, A., Mazzanti, C. M., Costa, M., & Caleo, M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104942 · Cited by 56 · see citing works
Kang, S. K., Markowitz, G. J., Kim, S. T., Johnston, M. V., & Kadam, S. D. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00173 · Cited by 53 · see citing works
Berntsson, S. G., Merrell, R. T., Amirian, E. S., Armstrong, G., Lachance, D. H., Smits, A., Zhou, R., Jacobs, D. I., Wrensch, M., Olson, S. H., et al. (2018) · Journal of Neurology · doi:10.1007/s00415-018-8857-0 · Cited by 53 · see citing works
When Are Depolarizing GABAergic Responses Excitatory?
Kilb, W. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.747835 · Cited by 52 · see citing works
Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytes
Campbell, S. C., Muñoz‐Ballester, C., Chaunsali, L., Mills, W. A., Yang, J. H., Sontheimer, H. W., & Robel, S. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104628 · Cited by 49 · see citing works
Self-citationKeough, M. B., & Monje, M. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-111020-092702 · Cited by 46 · see citing works
Double-edged GABAergic synaptic transmission in seizures: The importance of chloride plasticity
Wang, Y., Wang, Y., & Chen, Z. (2018) · Brain Research · doi:10.1016/j.brainres.2018.09.008 · Cited by 47 · see citing works
Multi‐omics technologies and molecular biomarkers in brain tumor‐related epilepsy
Du, Y., Li, R., Fu, D., Zhang, B., Cui, A., Shao, Y., Lai, Z., Chen, R., Chen, B., Wang, Z., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14717 · Cited by 45 · see citing works
Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales
Meyer, J. F., Yu, K., Luna-Figueroa, E., Deneen, B., & Noebels, J. L. (2024) · Nature Communications · doi:10.1038/s41467-024-48757-5 · Cited by 45 · see citing works
Expanding Spectrum of Sodium Potassium Chloride Co-transporters in the Pathophysiology of Diseases
Jaggi, A. S., Kaur, A., Bali, A., & Singh, N. (2015) · Current Neuropharmacology · doi:10.2174/1570159x13666150205130359 · Cited by 45 · see citing works
Neuron–Glial Interactions in Health and Brain Cancer
Pan, Y., & Monje, M. (2022) · Advanced Biology · doi:10.1002/adbi.202200122 · Cited by 45 · see citing works
Düsterwald, K. M., Currin, C. B., Burman, R. J., Akerman, C. J., Kay, A. R., & Raimondo, J. V. (2018) · eLife · doi:10.7554/elife.39575 · Cited by 44 · see citing works
What is New in the Management of Epilepsy in Gliomas?
Rudà, R., & Soffietti, R. (2015) · Current Treatment Options in Neurology · doi:10.1007/s11940-015-0351-8 · Cited by 43 · see citing works
Role of Astrocytes in Post-traumatic Epilepsy
Xu, S., Sun, Q., Fan, J., Jiang, Y., Yang, W., Cui, Y., Yu, Z., Jiang, H., & Li, B. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.01149 · Cited by 41 · see citing works
Sánchez-Aguilera, A., Masmudi‐Martín, M., Navas-Olivé, A., Baena, P., Hernández-Oliver, C., Priego, N., Cordón-Barris, L., Álvaro‐Espinosa, L., García‐Martín, S., Martı́nez, S., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.07.010 · Cited by 42 · see citing works
Cardona, A. F., Rojas, L., Wills, B., Bernal, L., Ruíz-Patiño, A., Arrieta, O. G., Hakim, E. J., Hakim, F., Mejía, J. A., Useche, N., et al. (2017) · Journal of Neuro-Oncology · doi:10.1007/s11060-017-2660-0 · Cited by 40 · see citing works
Stone, T. J., Rowell, R., Jayasekera, B. A. P., Cunningham, M. O., & Jacques, T. S. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12459 · Cited by 40 · see citing works
Synaptic Communication in Brain Cancer
Monje, M. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0646 · Cited by 40 · see citing works
Ion Channels and Their Role in the Pathophysiology of Gliomas
Takayasu, T., Kurisu, K., Esquenazi, Y., & Ballester, L. Y. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0929 · Cited by 40 · see citing works
Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma
Hills, K., Kostarelos, K., & Wykes, R. C. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.903115 · Cited by 42 · see citing works
Crosstalk between cancer cells and the nervous system
Huang, M., Gong, G., Deng, Y., Long, X., Long, W., Liu, Q., Zhao, W., & Chen, R. (2023) · Medicine Advances · doi:10.1002/med4.27 · Cited by 39 · see citing works
Robinson, S., Winer, J. L., Berkner, J., Chan, L. A. S., Denson, J. L., Maxwell, J. R., Yang, Y., Sillerud, L. O., Tasker, R. C., Meehan, W. P., III, et al. (2016) · Journal of Neurosurgery Pediatrics · doi:10.3171/2015.10.peds15554 · Cited by 38 · see citing works
Goldstein, E. D., & Feyissa, A. M. (2018) · Neurologia i Neurochirurgia Polska · doi:10.1016/j.pjnns.2018.06.001 · Cited by 40 · see citing works
The neuroscience of brain cancers
Monje, M. (2025) · Neuron · doi:10.1016/j.neuron.2025.07.012 · Cited by 40 · see citing works
Jantzie, L. L., Getsy, P. M., Denson, J. L., Firl, D. J., Maxwell, J. R., Rogers, D. A., Wilson, C. G., & Robinson, S. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00347 · Cited by 35 · see citing works
Old Stars and New Players in the Brain Tumor Microenvironment
Parmigiani, E., Scalera, M., Mori, E., Tantillo, E., & Vannini, E. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.709917 · Cited by 33 · see citing works
Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition
Goldberg, A. R., Dovas, A., Torres, D., Pereira, B., Viswanathan, A., Sharma, S. D., Mela, A., Merricks, E. M., Megino‐Luque, C., McInvale, J. J., et al. (2024) · Neuron · doi:10.1016/j.neuron.2024.12.026 · Cited by 34 · see citing works
Ion Channels in Gliomas—From Molecular Basis to Treatment
Elias, A. F., Lin, B. C., & Piggott, B. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032530 · Cited by 32 · see citing works
Vannini, E., Olimpico, F., Middei, S., Ammassari‐Teule, M., de Graaf, E. L., McDonnell, L. A., Schmidt, G., Fabbri, A., Fiorentini, C., Baroncelli, L., et al. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now114 · Cited by 30 · see citing works
Mechanisms and therapeutic implications of glioma-neuron interactions
Wang, Y., Wang, Y., Bao, H., Wang, Z., & Jiang, T. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217884 · Cited by 29 · see citing works
Peritumoural glutamate correlates with post-operative seizures in supratentorial gliomas
Neal, A. J., Yuen, T., Bjorksten, A. R., Kwan, P., O'Brien, T. J., & Morokoff, A. P. (2016) · Journal of Neuro-Oncology · doi:10.1007/s11060-016-2169-y · Cited by 28 · see citing works
Venkataramani, V., Yang, Y., Ille, S., Suchorska, B., Loges, S., Tost, H., Sahm, F., Pfister, S. M., Trumpp, A., Krieg, S. M., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0194 · Cited by 29 · see citing works
Cancer neuroscience: signaling pathways and new therapeutic strategies for cancer
Zhang, S., Yuan, L., Lin, P., Yang, G., Zhou, X., Jinfu, X., Wu, M., & Huang, Y. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02364-y · Cited by 26 · see citing works
In vitro ictogenesis is stochastic at the single neuron level
Lau, L. A., Staley, K. J., & Lillis, K. P. (2021) · Brain · doi:10.1093/brain/awab312 · Cited by 25 · see citing works
Gill, B. J. A., Khan, F. A., Goldberg, A., Merricks, E. M., Wu, X., Sosunov, A. A., Sudhakar, T. D., Dovas, A., Lado, W. E., Michalak, A. J., et al. (2022) · Brain · doi:10.1093/brain/awac168 · Cited by 26 · see citing works
Neurons as stromal drivers of nervous system cancer formation and progression
Anastasaki, C., Gao, Y., & Gutmann, D. H. (2023) · Developmental Cell · doi:10.1016/j.devcel.2022.12.011 · Cited by 25 · see citing works
Li, X., & Hong, M. (2019) · The Kaohsiung Journal of Medical Sciences · doi:10.1002/kjm2.12139 · Cited by 25 · see citing works
Advancing glioblastoma therapy: Learning from the past and innovations for the future
Rana, M., Liou, K.-C., Thakur, A., Nepali, K., & Liou, J. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217601 · Cited by 24 · see citing works
The role of SLC12A family of cation-chloride cotransporters and drug discovery methodologies
Zhang, S., Azlan, N. F. M., Josiah, S. S., Zhou, J., Xiaoxia, Z., Jie, L., Zhang, Y., Dai, C., Liang, D., Li, P., et al. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.09.002 · Cited by 23 · see citing works
Lia, A., Spiezio, A. D., Vitalini, L., Tore, M., Puja, G., & Losi, G. (2023) · Life · doi:10.3390/life13102038 · Cited by 23 · see citing works
Epilepsy in gliomas: recent insights into risk factors and molecular pathways
Rudà, R., Bruno, F., & Pellerino, A. (2023) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001214 · Cited by 22 · see citing works
New strategies for managing adult gliomas
Kirby, A. J., & Finnerty, G. T. (2020) · Journal of Neurology · doi:10.1007/s00415-020-09884-3 · Cited by 22 · see citing works
Muñoz‐Ballester, C., Mahmutovic, D., Rafiqzad, Y., Korot, A., & Robel, S. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.821885 · Cited by 20 · see citing works
Self-citationStella, M., Baiardi, G., Pasquariello, S., Sacco, F., Dellacasagrande, I., Corsaro, A., Mattioli, F., & Barbieri, F. (2023) · Biomedicines · doi:10.3390/biomedicines11020582 · Cited by 20 · see citing works
Picart, T., & Hervey‐Jumper, S. L. (2024) · Journal of Neuro-Oncology · doi:10.1007/s11060-024-04719-x · Cited by 19 · see citing works
Clasadonte, J., Morel, L., Barrios-Camacho, C. M., Chiang, M. S. R., Zhang, J., Iyer, L. K., Haydon, P. G., & Yang, Y. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.03.024 · Cited by 19 · see citing works
Animal models and human tissue compared to better understand and treat the epilepsies
Milior, G., Morin‐Brureau, M., Pallud, J., Miles, R., & Huberfeld, G. (2023) · Epilepsia · doi:10.1111/epi.17552 · Cited by 19 · see citing works
Glioblastoma remodeling of neural circuits in the human brain decreases survivalPreprint
Krishna, S., Choudhury, A., Seo, K., Ni, L., Kakaizada, S., Lee, A. J., Aabedi, A. A., Cao, C., Sudharshan, R., Egladyous, A., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.18.431915 · Cited by 19 · see citing works
Microenvironmental Drivers of Glioma Progression
Jang, H. J., & Park, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052108 · Cited by 18 · see citing works
Gill, B. J. A., Wu, X., Khan, F. A., Sosunov, A. A., Liou, J.-Y., Dovas, A., Eissa, T. L., Banu, M. A., Bateman, L. M., McKhann, G. M., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104676 · Cited by 18 · see citing works
Beta-Amyloid (Aβ1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus
Lam, P., Vinnakota, C., Guzmán, B. C., Newland, J., Peppercorn, K., Tate, W. P., Waldvogel, H. J., Faull, R. L. M., & Kwakowsky, A. (2022) · Molecules · doi:10.3390/molecules27082440 · Cited by 17 · see citing works
Glioma facilitates the epileptic and tumor-suppressive gene expressions in the surrounding region
Komiyama, K., Iijima, K., Kawabata‐Iwakawa, R., Fujihara, K., Kakizaki, T., Yanagawa, Y., Yoshimoto, Y., & Miyata, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-10753-4 · Cited by 18 · see citing works
Neurotransmitter power plays: the synaptic communication nexus shaping brain cancer
Mondal, J., & Huse, J. T. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02009-9 · Cited by 17 · see citing works
The complex molecular epileptogenesis landscape of glioblastoma
Soeung, V., Puchalski, R. B., & Noebels, J. L. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101691 · Cited by 18 · see citing works
The Neural Regulation of Cancer
Gillespie, S. M., & Monje, M. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033349 · Cited by 19 · see citing works
Reprogramming neural‑tumor crosstalk: emerging therapeutic dimensions and targeting strategies
Liu, Q., Dong, Z.-K., Wang, Y., & Jin, W. (2025) · Military Medical Research · doi:10.1186/s40779-025-00661-9 · Cited by 17 · see citing works
SLC12A5 as a novel potential biomarker of glioblastoma multiforme
Chen, J., Handong, W., Deng, C., & Fei, M. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08371-y · Cited by 16 · see citing works
Progress in cancer neuroscience
Lan, Y., Zou, S., Wang, W., Chen, Q., & Zhu, Y. (2023) · MedComm · doi:10.1002/mco2.431 · Cited by 18 · see citing works
Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors
de Jong, J. M., Broekaart, D. W. M., Bongaarts, A., Mühlebner, A., Mills, J. D., van Vliet, E. A., & Aronica, E. (2022) · Biomedicines · doi:10.3390/biomedicines10102475 · Cited by 14 · see citing works
- Authors
- Campbell, S. L., Robel, S., Cuddapah, V. A., Robert, S., Buckingham, S. C., Kahle, K. T., & Sontheimer, H.
- Affiliations
- University of Alabama at Birmingham (US)
- Boston Children's Hospital (US)
- Corresponding author
- Sontheimer, Harald
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2014-07-26
- Volume
- 63
- Issue
- 1
- Pages
- 23-36
- ISSN
- 0894-1491 (ISSN-L)
- PMC
- PMC4237714
- OpenAlex
- W1562543772
- Cited by
- 185
- References
- 53
- Citations by year
- 2026: 21 · 2025: 32 · 2024: 18 · 2023: 28 · 2022: 14 · 2021: 6 · 2020: 16 · 2019: 12 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 8
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5R01-NS036692, 2R01-NS052634, 5T32NS048039-03)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- tumor-associated epilepsy, glioma, GABAergic disinhibition, parvalbumin interneurons, intracellular chloride, GABAergic inhibition, SLC7A11, glutamate release, epileptogenesis, GABAA receptor, therapeutic target
- MeSH terms
- K Cl- Cotransporters, Animals, Brain Neoplasms, Epilepsy, Female, gamma-Aminobutyric Acid, Glioma, Interneurons, Male, Synaptic Transmission, Neurons, Receptors, GABA-A, Symporters, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
