Reactive Astrogliosis Causes the Development of Spontaneous Seizures
Open accessAbstract
Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of β1-integrin (Itgβ1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted β1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl − gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
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PNNs are intact in an astrocyte-specific beta integrin knockout (β1−/−) mouse, a genetic model of astrogliosis and spontaneous seizures.
“Secondly, PNNs are intact in an astrocyte-specific beta integrin knockout (β1−/−) mouse (Fig. 4d−g, Supplementary Fig. 1e), which is a genetic model of astrogliosis and spontaneous seizures31.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [31]
Cites
Astrocytes: Biology and pathology
Sofroniew, M. V., & Vinters, H. V. (2010) · Acta Neuropathologica · doi:10.1007/s00401-009-0619-8 · Cited by 5,196 · see citing works
Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129 · see citing works
Molecular dissection of reactive astrogliosis and glial scar formation
Sofroniew, M. V. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.08.002 · Cited by 2,594 · see citing works
Astrocytes, from brain glue to communication elements: the revolution continues
Volterra, A., & Meldolesi, J. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1722 · Cited by 1,763 · see citing works
Standards for epidemiologic studies and surveillance of epilepsy
Thurman, D. J., Beghi, E., Begley, C. E., Berg, A. T., Buchhalter, J., Ding, D., Hesdorffer, D. C., Hauser, W. A., Kazis, L. E., Kobau, R., et al. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03121.x · Cited by 1,015 · 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
Lehre, K. P., Levy, L., Ottersen, O. P., Storm‐Mathisen, J., & Danbolt, N. C. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-03-01835.1995 · Cited by 890 · see citing works
Self-citationGlia and epilepsy: excitability and inflammation
Devinsky, O., Vezzani, A., Najjar, S., de Lanerolle, N. C., & Rogawski, M. A. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.008 · Cited by 868 · see citing works
Cation-chloride cotransporters in neuronal development, plasticity and disease
Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M., & Voipio, J. (2014) · Nature reviews. Neuroscience · doi:10.1038/nrn3819 · Cited by 750 · see citing works
hGFAP‐cre transgenic mice for manipulation of glial and neuronal function in vivo
Zhuo, L., Theis, M., Álvarez-Maya, I., Brenner, M., Willecke, K., & Messing, A. (2001) · genesis · doi:10.1002/gene.10008 · Cited by 660 · see citing works
Djukic, B., Casper, K. B., Philpot, B. D., Chin, L., & McCarthy, K. D. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0723-07.2007 · Cited by 623 · 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
Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice
Goebbels, S., Bormuth, I., Bode, U., Hermanson, O., Schwab, M. H., & Nave, K. (2006) · genesis · doi:10.1002/dvg.20256 · Cited by 579 · 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-citationMechanisms of epileptogenesis: a convergence on neural circuit dysfunction
Goldberg, E. M., & Coulter, D. A. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3482 · Cited by 542 · see citing works
Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex
Seiffert, E., Dreier, J. P., Ivens, S., Bechmann, I., Tomkins‐Netzer, O., Heinemann, U., & Friedman, A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1751-04.2004 · Cited by 518 · see citing works
Selective induction of astrocytic gliosis generates deficits in neuronal inhibition
Ortinski, P. I., Dong, J., Mungenast, A., Yue, C., Takano, H., Watson, D. J., Haydon, P. G., & Coulter, D. A. (2010) · Nature Neuroscience · doi:10.1038/nn.2535 · Cited by 495 · see citing works
Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis
Ferrini, F., Trang, T., Mattioli, T.-A. M., Laffray, S., Del’Guidice, T., Lorenzo, L.-É., Castonguay, A., Doyon, N., Zhang, W., Godin, A. G., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3295 · Cited by 441 · see citing works
Roles 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
Mechanisms of neocortical epileptogenesis in vitro
Gutnick, M. J., Connors, B. W., & Prince, D. A. (1982) · Journal of Neurophysiology · doi:10.1152/jn.1982.48.6.1321 · Cited by 403 · see citing works
Astrocytes in the Epileptic Brain
Wetherington, J. P., Serrano, G. E., & Dingledine, R. J. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.002 · Cited by 391 · see citing works
Potocnik, A. J., Brakebusch, C., & Fässler, R. (2000) · Immunity · doi:10.1016/s1074-7613(00)80216-2 · Cited by 379 · see citing works
Schachtrup, K., Ryu, J. K., Helmrick, M. J., Vagena, E., Galanakis, D. K., Degen, J. L., Margolis, R. U., & Akassoglou, K. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0137-10.2010 · Cited by 371 · see citing works
Modular Propagation of Epileptiform Activity: Evidence for an Inhibitory Veto in Neocortex
Trevelyan, A. J., Sussillo, D., Watson, B. O., & Yuste, R. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.2787-06.2006 · Cited by 344 · see citing works
Olsen, M. L., & Sontheimer, H. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05615.x · Cited by 323 · see citing works
Self-citationLiu, W., Tang, Y., & Feng, J. (2011) · Life Sciences · doi:10.1016/j.lfs.2011.05.011 · Cited by 303 · see citing works
NMDA 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
Astrocytic regulation of glutamate homeostasis in epilepsy
Coulter, D. A., & Eid, T. (2012) · Glia · doi:10.1002/glia.22341 · Cited by 293 · see citing works
Astrocyte dysfunction in epilepsy
Seifert, G., Carmignoto, G., & Steinhäuser, C. (2009) · Brain Research Reviews · doi:10.1016/j.brainresrev.2009.10.004 · Cited by 287 · see citing works
Larsen, B. R., Assentoft, M., Cotrina, M. L., Hua, S. Z., Nedergaard, M., Kaila, K., Voipio, J., & MacAulay, N. (2014) · Glia · doi:10.1002/glia.22629 · Cited by 269 · see citing works
Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering
Thrane, V. R., Thrane, A. S., Wang, F., Cotrina, M. L., Smith, N., Chen, M. J., Xu, Q., Kang, N., Fujita, T., Nagelhus, E. A., et al. (2013) · Nature Medicine · doi:10.1038/nm.3400 · Cited by 265 · see citing works
Blood‐brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy
Heinemann, U., Kaufer, D., & Friedman, A. (2012) · Glia · doi:10.1002/glia.22311 · Cited by 255 · see citing works
Properties of human glial cells associated with epileptic seizure foci
Bordey, A., & Sontheimer, H. W. (1998) · Epilepsy Research · doi:10.1016/s0920-1211(98)00059-x · Cited by 249 · see citing works
Self-citationNeurological Diseases as Primary Gliopathies: A Reassessment of Neurocentrism
Verkhratsky, A., Sofroniew, M. V., Messing, A., deLanerolle, N. C., Rempe, D. A., Rodriguez, J. J., & Nedergaard, M. (2012) · ASN NEURO · doi:10.1042/an20120010 · Cited by 247 · see citing works
Molecular Mechanisms of Ischemic Cerebral Edema: Role of Electroneutral Ion Transport
Kahle, K. T., Simard, J. M., Staley, K. J., Nahed, B. V., Jones, P. S., & Sun, D. (2009) · Physiology · doi:10.1152/physiol.00015.2009 · Cited by 242 · see citing works
AMPA receptors as a molecular target in epilepsy therapy
Rogawski, M. A. (2013) · Acta Neurologica Scandinavica · doi:10.1111/ane.12099 · Cited by 232 · see citing works
Modulation of neuronal activity by phosphorylation of the K–Cl cotransporter KCC2
Kahle, K. T., Deeb, T. Z., Puskarjov, M., Silayeva, L., Liang, B., Kaila, K., & Moss, S. J. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2013.08.006 · Cited by 224 · see citing works
Ransom, C. B., & Sontheimer, H. W. (1995) · Journal of Neurophysiology · doi:10.1152/jn.1995.73.1.333 · Cited by 219 · see citing works
Self-citationPinto, D. J., Patrick, S. L., Huang, W. C., et al. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2278-05.2005 · Cited by 217 · see citing works
Campbell, S. L., Robel, S., Cuddapah, V. A., Robert, S., Buckingham, S. C., Kahle, K. T., & Sontheimer, H. (2015) · Glia · doi:10.1002/glia.22730 · Cited by 185 · see citing works
Self-citationBrandt, C., Nozadze, M., Heuchert, N., Rattka, M., & Löscher, W. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0633-10.2010 · Cited by 179 · see citing works
Pedersen, S. F., O’Donnell, M. E., Anderson, S. E., & Cala, P. M. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00782.2005 · Cited by 165 · see citing works
Postnatal Development of Ionic Currents in Rat Hippocampal Astrocytes In Situ
Bordey, A., & Sontheimer, H. W. (1997) · Journal of Neurophysiology · doi:10.1152/jn.1997.78.1.461 · Cited by 159 · see citing works
Self-citationNeuron–astrocyte signaling and epilepsy
Seifert, G., & Steinhäuser, C. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.08.024 · Cited by 156 · see citing works
Adams, R., Schachtrup, C., Davalos, D., Tsigelny, I. F., & Akassoglou, K. (2007) · Current Medicinal Chemistry · doi:10.2174/092986707782360015 · Cited by 150 · see citing works
Electrophysiological Characteristics of Reactive Astrocytes in Experimental Cortical Dysplasia
Bordey, A., Lyons, S. A., Hablitz, J. J., & Sontheimer, H. W. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.85.4.1719 · Cited by 149 · see citing works
Self-citationThe role of Na–K–Cl co–transporter in cerebral ischemia
Chen, H., & Sun, D. (2005) · Neurological Research · doi:10.1179/016164105x25243 · Cited by 139 · see citing works
Astrocyte calcium signaling and epilepsy
Carmignoto, G., & Haydon, P. G. (2012) · Glia · doi:10.1002/glia.22318 · Cited by 129 · see citing works
Cytoskeletal Anchoring of GLAST Determines Susceptibility to Brain Damage
Sullivan, S. M., Lee, A., Björkman, S. T., Miller, S. M., Sullivan, R. K. P., Poronnik, P., Colditz, P. B., & Pow, D. V. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704152200 · Cited by 128 · see citing works
Conditional deletion of β1‐integrin in astroglia causes partial reactive gliosis
Robel, S., Mori, T., Zoubaa, S., Schlegel, J., Sirko, S., Faissner, A., Goebbels, S., Dimou, L., & Götz, M. (2009) · Glia · doi:10.1002/glia.20876 · Cited by 120 · see citing works
Self-citationFunctional expression of Kir4.1 channels in spinal cord astrocytes
Olsen, M. L., Higashimori, H., Campbell, S. L., Hablitz, J. J., & Sontheimer, H. W. (2005) · Glia · doi:10.1002/glia.20312 · Cited by 117 · see citing works
Self-citationJanigro, D. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03472.x · Cited by 115 · see citing works
Frigerio, F., Frasca, A., Weissberg, I., Parrella, S., Friedman, A., Vezzani, A., & Noè, F. M. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03666.x · Cited by 115 · see citing works
Rose, C. R., & Karus, C. (2013) · Glia · doi:10.1002/glia.22492 · Cited by 112 · see citing works
Glial K+ Clearance and Cell Swelling: Key Roles for Cotransporters and Pumps
MacAulay, N., & Zeuthen, T. (2012) · Neurochemical Research · doi:10.1007/s11064-012-0731-3 · Cited by 110 · see citing works
Role of Kir4.1 channels in growth control of glia
Higashimori, H., & Sontheimer, H. (2007) · Glia · doi:10.1002/glia.20574 · Cited by 101 · see citing works
Self-citationNKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade
Lu, K., Cheng, N.-C., Wu, C.-Y., & Yang, Y.-L. (2008) · Critical Care Medicine · doi:10.1097/ccm.0b013e31816590c4 · Cited by 97 · see citing works
Robel, S., Bardehle, S., Lepier, A., Brakebusch, C., & Götz, M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2696-11.2011 · Cited by 93 · see citing works
Self-citationOlsen, M. L., Campbell, S. L., & Sontheimer, H. W. (2007) · Journal of Neurophysiology · doi:10.1152/jn.00340.2007 · Cited by 90 · see citing works
Self-citationDo seizures and epileptic activity worsen epilepsy and deteriorate cognitive function?
AVANZINI, G., Depaulis, A., Tassinari, A., & de Curtis, M. (2013) · Epilepsia · doi:10.1111/epi.12418 · Cited by 77 · see citing works
The role of glial membrane ion channels in seizures and epileptogenesis
D’Ambrosio, R. (2004) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2004.05.004 · Cited by 75 · see citing works
In search of models of pharmacoresistant epilepsy
Wahab, A., Albus, K., Gabriel, S., et al. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02632.x · Cited by 73 · see citing works
Basic mechanisms of focal epilepsies
Jefferys, J. G. R. (1990) · Experimental Physiology · doi:10.1113/expphysiol.1990.sp003390 · Cited by 73 · see citing works
DNA methylation functions as a critical regulator of Kir4.1 expression during CNS development
Nwaobi, S. E., Lin, E., Peramsetty, S. R., & Olsen, M. L. (2014) · Glia · doi:10.1002/glia.22613 · Cited by 57 · see citing works
Holmseth, S., Dehnes, Y., Bjørnsen, L. P., Boulland, J., Furness, D. N., Bergles, D. E., & Danbolt, N. C. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.07.022 · Cited by 46 · see citing works
Self-citationSheean, R. K., Lau, C. L., Shin, Y. S., et al. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.09.043 · Cited by 39 · see citing works
Synthesis and release of L-serine by rat astroglia-rich primary cultures
Verleysdonk, S., & Hamprecht, B. (2000) · Glia · doi:10.1002/(sici)1098-1136(200003)30:1 · Cited by 37 · see citing works
Li, Y., Zhou, Y., & Danbolt, N. C. (2012) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155412458589 · Cited by 29 · see citing works
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- Authors
- Robel, S., Buckingham, S. C., Boni, J. L., Campbell, S. L., Danbolt, N. C., Riedemann, T., Sutor, B., & Sontheimer, H.
- Affiliations
- University of Alabama at Birmingham (US)
- University of Oslo (NO)
- Physiologisches Institut (DE)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-02-25
- Volume
- 35
- Issue
- 8
- Pages
- 3330-3345
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4339349
- OpenAlex
- W1984050978
- Cited by
- 283
- References
- 68
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 27 · 2023: 20 · 2022: 28 · 2021: 29 · 2020: 37 · 2019: 25 · 2018: 22 · 2017: 22 · 2016: 25 · 2015: 8
- FWCI
- 20.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Brain Tumor Association
- Epilepsy Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5r01ns031234-18, 5RO1NS031234)
- National Institute of Neurological Disorders and Stroke (R01-NS031234, R01NS052634, F31NS074597, 5R01NS031234, R01NS036692, R01NS082851)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD038985)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- reactive astrogliosis, epileptogenesis, spontaneous seizures, beta1 integrin, NKCC1, KCC2, cation-chloride cotransporters, GABAergic inhibition, neuronal hyperexcitability, bumetanide, astrocyte-neuron interaction
- MeSH terms
- K Cl- Cotransporters, Action Potentials, Animals, Astrocytes, Blood-Brain Barrier, Cells, Cultured, Gliosis, Neurons, Seizures, Glutamic Acid, Integrin beta1, Symporters, Mice, Solute Carrier Family 12, Member 2
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