Reactive microglia are the major source of tumor necrosis factor alpha and contribute to astrocyte dysfunction and acute seizures in experimental temporal lobe epilepsy.
[en] Extensive microglia reactivity has been well described in human and experimental temporal lobe epilepsy (TLE). To date, however, it is not clear whether and based on which molecular mechanisms microglia contribute to the development and progression of focal epilepsy. Astroglial gap junction coupled networks play an important role in regulating neuronal activity and loss of interastrocytic coupling causally contributes to TLE. Here, we show in the unilateral intracortical kainate (KA) mouse model of TLE that reactive microglia are primary producers of tumor necrosis factor (TNF)α and contribute to astrocyte dysfunction and severity of status epilepticus (SE). Immunohistochemical analyses revealed pronounced and persistent microglia reactivity, which already started 4 h after KA-induced SE. Partial depletion of microglia using a colony stimulating factor 1 receptor inhibitor prevented early astrocyte uncoupling and attenuated the severity of SE, but increased the mortality of epileptic mice following surgery. Using microglia-specific inducible TNFα knockout mice we identified microglia as the major source of TNFα during early epileptogenesis. Importantly, microglia-specific TNFα knockout prevented SE-induced gap junction uncoupling in astrocytes. Continuous telemetric EEG recordings revealed that during the first 4 weeks after SE induction, microglial TNFα did not significantly contribute to spontaneous generalized seizure activity. Moreover, the absence of microglial TNFα did not affect the development of hippocampal sclerosis but attenuated gliosis. Taken together, these data implicate reactive microglia in astrocyte dysfunction and network hyperexcitability after an epileptogenic insult.
Disciplines :
Neurology
Author, co-author :
Henning, Lukas
Antony, Henrike
Breuer, Annika
Müller, Julia
Seifert, Gerald
Audinat, Etienne
Singh, Parmveer
Brosseron, Frederic
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Steinhäuser, Christian
Bedner, Peter
External co-authors :
yes
Language :
English
Title :
Reactive microglia are the major source of tumor necrosis factor alpha and contribute to astrocyte dysfunction and acute seizures in experimental temporal lobe epilepsy.
Publication date :
2023
Journal title :
Glia
ISSN :
1098-1136
Publisher :
John Wiley & Sons, Hoboken, United States - New York
Altmann, A., Ryten, M., Di Nunzio, M., Ravizza, T., Tolomeo, D., Reynolds, R. H., Somani, A., Bacigaluppi, M., Iori, V., Micotti, E., Di Sapia, R., Cerovic, M., Palma, E., Ruffolo, G., Botía, J. A., Absil, J., Alhusaini, S., Alvim, M., Auvinen, P., … Sisodiya, S. M. (2022). A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies. Neuropathology and Applied Neurobiology, 48(1), e12758. https://doi.org/10.1111/nan.12758
Aronica, E., Boer, K., van Vliet, E. A., Redeker, S., Baayen, J. C., Spliet, W. G. M. van Rijen, P. C., Troost, D., Lopes da Silva, F. H., Wadman, W. J., & Gorter, J. A. (2007). Complement activation in experimental and human temporal lobe epilepsy. Neurobiology of Disease, 26(3), 497–511. https://doi.org/10.1016/j.nbd.2007.01.015
Aronica, E., Bauer, S., Bozzi, Y., Caleo, M., Dingledine, R., Gorter, J. A., Henshall, D. C., Kaufer, D., Koh, S., Löscher, W., Louboutin, J.-P., Mishto, M., Norwood, B. A., Palma, E., Poulter, M. O., Terrone, G., Vezzani, A., & Kaminski, R. M. (2017). Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia, 58, 27–38. https://doi.org/10.1111/epi.13783
Avignone, E., Ulmann, L., Levavasseur, F., Rassendren, F., & Audinat, E. (2008). Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. Journal of Neuroscience, 28(37), 9133–9144. https://doi.org/10.1523/JNEUROSCI.1820-08.2008
Balosso, S., Ravizza, T., Perego, C., Peschon, J., Campbell, I. L., De Simoni, M. G., & Vezzani, A. (2005). Tumor necrosis factor-α inhibits seizures in mice via p75 receptors. Annals of Neurology, 57(6), 804–812. https://doi.org/10.1002/ana.20480
Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., Ferretti, V., Reverte, I., Sanchini, C., Marrone, M. C., Giubettini, M., De Turris, V., Salerno, D., Garofalo, S., St-Pierre, M. K., Carrier, M., Renzi, M., Pagani, F., Modi, B., … Ragozzino, D. (2022). Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia, 70(1), 173–195. https://doi.org/10.1002/glia.24101
Bedner, P., Dupper, A., Hüttmann, K., Müller, J., Herde, M. K., Dublin, P., Deshpande, T., Schramm, J., Häussler, C. A., Henneberger, C., Theis, M., & Steinhäuser, C. (2015). Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain, 138(5), 1208–1222. https://doi.org/10.1093/brain/awv067
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., Weissman, I. L., Chang, E. F., Li, G., Grant, G. A., Hayden Gephart, M. G., & Barres, B. A. (2016). New tools for studying microglia in the mouse and human CNS. Proceedings of the National Academy of Sciences, 113(12), E1738–E1746. https://doi.org/10.1073/pnas.1525528113
Benson, M. J., Manzanero, S., & Borges, K. (2015). Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia, 56(6), 895–905. https://doi.org/10.1111/epi.12960
Blümcke, I., Beck, H., Lie, A. A., & Wiestler, O. D. (1999). Molecular neuropathology of human mesial temporal lobe epilepsy. Epilepsy Research, 36(2–3), 205–223. https://doi.org/10.1016/S0920-1211(99)00052-2
Bogie, J. F., Boelen, E., Louagie, E., Delputte, P., Elewaut, D., van Horssen, J. Hendriks, J. J., & Hellings, N. (2018). CD169 is a marker for highly pathogenic phagocytes in multiple sclerosis. Multiple Sclerosis Journal, 24(3), 290–300. https://doi.org/10.1177/1352458517698759
Brambilla, R., Ashbaugh, J. J., Magliozzi, R., Dellarole, A., Karmally, S., Szymkowski, D. E., & Bethea, J. R. (2011). Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain, 134(9), 2736–2754. https://doi.org/10.1093/brain/awr199
Broekaart, D. W. M., Anink, J. J., Baayen, J. C., Idema, S., de Vries, H. E., Aronica, E., Gorter, J. J., & van Vliet, E. A. (2018). Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression. Epilepsia, 59(10), 1931–1944. https://doi.org/10.1111/epi.14550
Bruce, A. J., Boling, W., Kindy, M. S., Peschon, J., Kraemer, P. J., Carpenter, M. K., Holtsberg, F. W., & Mattson, M. P. (1996). Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Medicine, 2(7), 788–794. https://doi.org/10.1038/nm0796-788
Butovsky, O., Siddiqui, S., Gabriely, G., Lanser, A. J., Dake, B., Murugaiyan, G., Doykan, C. E., Wu, P. M., Gali, R. R., Iyer, L. K., Lawson, R., Berry, J., Krichevsky, A. M., Cudkowicz, M. E., & Weiner, H. L. (2012). Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. Journal of Clinical Investigation, 122(9), 3063–3087. https://doi.org/10.1172/JCI62636
Coulter, D. A., & Steinhauser, C. (2015). Role of Astrocytes in Epilepsy. Cold Spring Harbor Perspectives in Medicine, 5(3), a022434. https://doi.org/10.1101/cshperspect.a022434
Dagher, N. N., Najafi, A. R., Kayala, K. M. N., Elmore, M. R. P., White, T. E., Medeiros, R., West, B. L., & Green, K. N. (2015). Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. Journal of Neuroinflammation, 12(1), 139. https://doi.org/10.1186/s12974-015-0366-9
De Simoni, M. G., Perego, C., Ravizza, T., Moneta, D., Conti, M., Marchesi, F., Garattini, S., & Vezzani, A. (2000). Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus: Cytokines in status epilepticus. European Journal of Neuroscience, 12(7), 2623–2633. https://doi.org/10.1046/j.1460-9568.2000.00140.x
Deshpande, T., Li, T., Herde, M. K., Becker, A., Vatter, H., Schwarz, M. K., Henneberger, C., Steinhäuser, C., & Bedner, P. (2017). Subcellular reorganization and altered phosphorylation of the astrocytic gap junction protein connexin43 in human and experimental temporal lobe epilepsy. Glia, 65(11), 1809–1820. https://doi.org/10.1002/glia.23196
Devinsky, O., Vezzani, A., Najjar, S., De Lanerolle, N. C., & Rogawski, M. A. (2013). Glia and epilepsy: Excitability and inflammation. Trends in Neurosciences, 36(3), 174–184. https://doi.org/10.1016/j.tins.2012.11.008
Di Nunzio, M., Di Sapia, R., Sorrentino, D., Kebede, V., Cerovic, M., & Gullotta, G. S., Bacigaluppi, M., Audinat, E., Marchi, N., Ravizza, T., Vezzani, A. (2021). Microglia proliferation plays distinct roles in acquired epilepsy depending on disease stages. Epilepsia, 62(8), 1931–1945. https://doi.org/10.1111/epi.16956
Dissing-Olesen, L., LeDue, J. M., Rungta, R. L., Hefendehl, J. K., Choi, H. B., & MacVicar, B. A. (2014). Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. Journal of Neuroscience, 34(32), 10511–10527. https://doi.org/10.1523/JNEUROSCI.0405-14.2014
Dong, Y., Fischer, R., Naudé, P. J. W., Maier, O., Nyakas, C., Duffey, M., Van der Zee, E. A., Dekens, D., Douwenga, W., Herrmann, A., Guenzi, E., Kontermann, R. E., Pfizenmaier, K., & Eisel, U. L. M. (2016). Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration. Proceedings of the National Academy of Sciences, 113(43), 12304–12309. https://doi.org/10.1073/pnas.1605195113
Escartin, C., Galea, E., Lakatos, A., O'Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., Allen, N. J., Araque, A., Barbeito, L., Barzilai, A., Bergles, D. E., Bonvento, G., Butt, A. M., Chen, W.-T., Cohen-Salmon, M., … Verkhratsky, A. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nature Neuroscience, 24(3), 312–325. https://doi.org/10.1038/s41593-020-00783-4
Eyo, U. B., Peng, J., Swiatkowski, P., Mukherjee, A., Bispo, A., & Wu, L.-J. (2014). Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. Journal of Neuroscience, 34(32), 10528–10540. https://doi.org/10.1523/JNEUROSCI.0416-14.2014
Feng, L., Murugan, M., Bosco, D. B., Liu, Y., Peng, J., Worrell, G. A., Wang, H-.L., Ta, L. E., Richardson, J. R., Shen Y., Wu, L. (2019). Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus. Glia, 67(8), 1434–1448. https://doi.org/10.1002/glia.23616
Fülle, L., Offermann, N., Hansen, J. N., Breithausen, B., Erazo, A. B., Schanz, O., Radau, L., Gondorf, F., Knöpper, K., Alferink, J., Abdullah, Z., Neumann, H., Weighardt, H., Henneberger, C., & Förster, I. (2018). CCL17 exerts a neuroimmune modulatory function and is expressed in hippocampal neurons. Glia, 66(10), 2246–2261. https://doi.org/10.1002/glia.23507
Gao, L., Brenner, D., Llorens-Bobadilla, E., Saiz-Castro, G., Frank, T., Wieghofer, P., Hill, O., Thiemann, M., Karray, S., Prinz, M., Weishaupt, J. H., & Martin-Villalba, A. (2015). Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice. Journal of Experimental Medicine, 212(4), 469–480. https://doi.org/10.1084/jem.20132423
Gershen, L. D., Zanotti-Fregonara, P., Dustin, I. H., Liow, J.-S., Hirvonen, J., Kreisl, W. C., Jenko, K. J. Inati, S. K., Fujita, M., Morse, C. L., Brouwer, C., Hong, J. S., Pike, V. W., Zoghbi, S. S.,Innis, R. B., & Theodore, W. H. (2015). Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurology, 72(8), 882–888. https://doi.org/10.1001/jamaneurol.2015.0941
Goldmann, T., Wieghofer, P., Müller, P. F., Wolf, Y., Varol, D., Yona, S., Brendecke, S. M., Kierdorf, K., Staszewski, O., Datta, M., Luedde, T., Heikenwalder, M., Jung, S., & Prinz, M. (2013). A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nature Neuroscience, 16(11), 1618–1626. https://doi.org/10.1038/nn.3531
Green, K. N., Crapser, J. D., & Hohsfield, L. A. (2020). To kill a microglia: A case for CSF1R inhibitors. Trends in Immunology, 41(9), 771–784. https://doi.org/10.1016/j.it.2020.07.001
Grivennikov, S., Tumanov, A., Liepinsh, D., Kruglov, A., Marakusha, B., Shakhov, A., Murakami, T. Drutskaya, L. N., Förster, I., Clausen, B. E., Tessarollo, L., Ryffel, B., Kuprash, D. V., & Nedospasov, S. A. (2005). Distinct and nonredundant in vivo functions of TNF produced by T cells and macrophages/neutrophils protective and deleterious effects. Immunity, 22(1), 93–104. https://doi.org/10.1016/S1074-7613(04)00379-6
Haghikia, A., Ladage, K., Lafênetre, P., Haghikia, A., Hinkerohe, D., Smikalla, D., Haase, C. G., Dermietzel, R., & Faustmann, P. M. (2008). Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells. Journal of Neuro-Oncology, 86(2), 143–152. https://doi.org/10.1007/s11060-007-9462-8
Hanisch, U.-K., & Kettenmann, H. (2007). Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience, 10(11), 1387–1394. https://doi.org/10.1038/nn1997
Henning, L., Steinhäuser, C., & Bedner, P. (2021). Initiation of experimental temporal lobe epilepsy by early astrocyte uncoupling is independent of TGFβR1/ALK5 signaling. Frontiers in Neurology, 12, 660591. https://doi.org/10.3389/fneur.2021.660591
Hiragi, T., Ikegaya, Y., & Koyama, R. (2018). Microglia after seizures and in epilepsy. Cell, 7(4), 26. https://doi.org/10.3390/cells7040026
Jurga, A. M., Paleczna, M., & Kuter, K. Z. (2020). Overview of general and discriminating markers of differential microglia phenotypes. Frontiers in Cellular Neuroscience, 14, 198. https://doi.org/10.3389/fncel.2020.00198
Kafitz, K. W., Meier, S. D., Stephan, J., & Rose, C. R. (2008). Developmental profile and properties of sulforhodamine 101—Labeled glial cells in acute brain slices of rat hippocampus. Journal of Neuroscience Methods, 169(1), 84–92. https://doi.org/10.1016/j.jneumeth.2007.11.022
Karamita, M., Barnum, C., Möbius, W., Tansey, M. G., Szymkowski, D. E., Lassmann, H., & Probert, L. (2017). Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia. JCI Insight, 2(8), e87455. https://doi.org/10.1172/jci.insight.87455
Käufer, C., Chhatbar, C., Bröer, S., Waltl, I., Ghita, L., Gerhauser, I., Kalinke, U., & Löscher, W. (2018). Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures. Proceedings of the National Academy of Sciences, 115(38), E8929–E8938. https://doi.org/10.1073/pnas.1806754115
Khan, D., Dupper, A., Deshpande, T., Graan, P. N. E. D., Steinhäuser, C., & Bedner, P. (2016). Experimental febrile seizures impair interastrocytic gap junction coupling in juvenile mice: Astrocyte uncoupling by febrile seizures. Journal of Neuroscience Research, 94(9), 804–813. https://doi.org/10.1002/jnr.23726
Kim, S. Y., & Nair, M. G. (2019). Macrophages in wound healing: Activation and plasticity. Immunology & Cell Biology, 97(3), 258–267. https://doi.org/10.1111/imcb.12236
Lehtimäki, K. A., Peltola, J., Koskikallio, E., Keränen, T., & Honkaniemi, J. (2003). Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures. Molecular Brain Research, 110(2), 253–260. https://doi.org/10.1016/S0169-328X(02)00654-X
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W. S., Peterson, T. C., Wilton, D. K., Frouin, A., Napier, B. A., Panicker, N., Kumar, M., Buckwalter, M. S., Rowitch, D. H., Dawson, V. L., Dawson, T. M., … Barres, B. A. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 541(7638), 481–487. https://doi.org/10.1038/nature21029
Liu, M., Jiang, L., Wen, M., Ke, Y., Tong, X., Huang, W., & Chen, R. (2020). Microglia depletion exacerbates acute seizures and hippocampal neuronal degeneration in mouse models of epilepsy. American Journal of Physiology-Cell Physiology, 319(3), C605–C610. https://doi.org/10.1152/ajpcell.00205.2020
Löscher, W., Potschka, H., Sisodiya, S. M., & Vezzani, A. (2020). Drug resistance in epilepsy: Clinical impact, potential mechanisms, and new innovative treatment options. Pharmacological Reviews, 72(3), 606–638. https://doi.org/10.1124/pr.120.019539
Même, W., Calvo, C., Froger, N., Ezan, P., Amigou, E., Koulakoff, A., & Giaume, C. (2006). Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: Potentiation by β-amyloid. The FASEB Journal, 20(3), 494–496. https://doi.org/10.1096/fj.05-4297fje
Merry, T. L., Brooks, A. E. S., Masson, S. W., Adams, S. E., Jaiswal, J. K., Jamieson, S. M. F., & Shepherd, P. R. (2020). The CSF1 receptor inhibitor pexidartinib (PLX3397) reduces tissue macrophage levels without affecting glucose homeostasis in mice. International Journal of Obesity, 44(1), 245–253. https://doi.org/10.1038/s41366-019-0355-7
Mirrione, M. M., Konomos, D. K., Gravanis, I., Dewey, S. L., Aguzzi, A., Heppner, F. L., & Tsirka, S. E. (2010). Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice. Neurobiology of Disease, 39(1), 85–97. https://doi.org/10.1016/j.nbd.2010.04.001
Morin-Brureau, M., Milior, G., Royer, J., Chali, F., Le Duigou, C., Savary, E., Blugeon, C., Jourdren, L., Akbar, D., Dupont, S., Navarro, V., Baulac, M., Bielle, F., Mathon, B., Clemenceau, S., & Miles, R. (2018). Microglial phenotypes in the human epileptic temporal lobe. Brain, 141(12), 3343–3360. https://doi.org/10.1093/brain/awy276
Nikolic, L., Shen, W., Nobili, P., Virenque, A., Ulmann, L., & Audinat, E. (2018). Blocking TNFα-driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis. Glia, 66(12), 2673–2683. https://doi.org/10.1002/glia.23519
Nolte, C., Matyash, M., Pivneva, T., Schipke, C. G., Ohlemeyer, C., Hanisch, U. K., Kirchhoff, F., & Kettenmann, H. (2001) GFAP promoter-controlled EGFP expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33(1):72–86.
Onodera, M., Meyer, J., Furukawa, K., Hiraoka, Y., Aida, T., Tanaka, K., Rose, C. R., & Matsui, K. (2021). Exacerbation of epilepsy by astrocyte alkalization and gap junction uncoupling. The Journal of Neuroscience, 41(10), 2106–2118. https://doi.org/10.1523/JNEUROSCI.2365-20.2020
Parkhurst, C. N., Yang, G., Ninan, I., Savas, J. N., Yates, J. R., Lafaille, J. J., Hempstead, B. L., Littman, D. R., & Gan, W.-B. (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 155(7), 1596–1609. https://doi.org/10.1016/j.cell.2013.11.030
Pascual, O., Ben Achour, S., Rostaing, P., Triller, A., & Bessis, A. (2012). Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proceedings of the National Academy of Sciences, 109(4), E197–E205. https://doi.org/10.1073/pnas.1111098109
Patel, D. C., Wallis, G., Dahle, E. J., McElroy, P. B., Thomson, K. E., Tesi, R. J., Szymkowski, D. E., West, P. J., Smeal, R. M., Patel, M., Fujinami, R. S., White, H. S., & Wilcox, K. S. (2017). Hippocampal TNFα signaling contributes to seizure generation in an infection-induced mouse model of limbic epilepsy. Eneuro, 4(2). https://doi.org/10.1523/ENEURO.0105-17.2017
Probert, L., Akassoglou, K., Pasparakis, M., Kontogeorgost, G., & Kollias, G. (1995). Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor a. Proceedings of the National Academy of Sciences, 92, 11294–11298.
Qin, C., Zhou, L.-Q., Ma, X.-T., Hu, Z.-W., Yang, S., Chen, M., Bosco, D. B., Wu, L.-J., & Tian, D.-S. (2019). Dual functions of microglia in ischemic stroke. Neuroscience Bulletin, 35(5), 921–933. https://doi.org/10.1007/s12264-019-00388-3
R Core Team. (2021). R: A language and environment for statistical computing. 7 Feb 2022. https://www.r-project.org/.
Rana, A., & Musto, A. E. (2018). The role of inflammation in the development of epilepsy. Journal of Neuroinflammation, 15(1), 144. https://doi.org/10.1186/s12974-018-1192-7
Riazi, K., Galic, M. A., Kuzmiski, J. B., Ho, W., Sharkey, K. A., & Pittman, Q. J. (2008). Microglial activation and TNF production mediate altered CNS excitability following peripheral inflammation. Proceedings of the National Academy of Sciences, 105(44), 17151–17156. https://doi.org/10.1073/pnas.0806682105
Rice, R. A., Spangenberg, E. E., Yamate-Morgan, H., Lee, R. J., Arora, R. P. S., Hernandez, M. X., Tenner, A. J., West, B. L., & Green, K. N. (2015). Elimination of microglia improves functional outcomes following extensive neuronal loss in the hippocampus. Journal of Neuroscience, 35(27), 9977–9989. https://doi.org/10.1523/JNEUROSCI.0336-15.2015
Rock, R. B., Gekker, G., Hu, S., Sheng, W. S., Cheeran, M., Lokensgard, J. R., & Peterson, P. K. (2004). Role of microglia in central nervous system infections. Clinical Microbiology Reviews, 17(4), 942–964. https://doi.org/10.1128/CMR.17.4.942-964.2004
Rodgers, K. M., Hutchinson, M. R., Northcutt, A., Maier, S. F., Watkins, L. R., & Barth, D. S. (2009). The cortical innate immune response increases local neuronal excitability leading to seizures. Brain, 132(9), 2478–2486. https://doi.org/10.1093/brain/awp177
Sanchez, J. M. S., DePaula-Silva, A. B., Doty, D. J., Truong, A., Libbey, J. E., & Fujinami, R. S. (2019). Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system. Journal of Neurovirology, 25(3), 415–421. https://doi.org/10.1007/s13365-019-00740-3
Sano, F., Shigetomi, E., Shinozaki, Y., Tsuzukiyama, H., Saito, K., Mikoshiba, K., Horiuchi, H., Cheung, D. L., Nabekura, J., Sugita, K., Aihara, M., & Koizumi, S. (2021). Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus. JCI Insight, 6(9), e135391. https://doi.org/10.1172/jci.insight.135391
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., Tinevez, J.-Y., White, D. J., Hartenstein, V., Eliceiri, K., Tomancak, P., & Cardona, A. (2012). Fiji: An open-source platform for biological-image analysis. Nature Methods, 9(7), 676–682. https://doi.org/10.1038/nmeth.2019
Seifert, G., Huttmann, K., Binder, D. K., Hartmann, C., Wyczynski, A., Neusch, C., & Steinhauser, C. (2009). Analysis of astroglial K+ channel expression in the developing hippocampus reveals a predominant role of the Kir4.1 subunit. Journal of Neuroscience, 29(23), 7474–7488. https://doi.org/10.1523/JNEUROSCI.3790-08.2009
Tukey, J. W. (1977). Exploratory data analysis. Addison-Wesley Pub. Co. http://archive.org/details/exploratorydataa00tuke_0
Varvel, N. H., Neher, J. J., Bosch, A., Wang, W., Ransohoff, R. M., Miller, R. J., & Dingledine, R. (2016). Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proceedings of the National Academy of Sciences, 113(38), E5665–E5674. https://doi.org/10.1073/pnas.1604263113
Vezzani, A., Conti, M., Luigi, A. D., Ravizza, T., Moneta, D., Marchesi, F., & Simoni, M. G. D. (1999). Interleukin-1ß immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: Functional evidence for enhancement of electrographic seizures. The Journal of Neuroscience, 19(12), 12–5065.
Vezzani, A., French, J., Bartfai, T., & Baram, T. Z. (2011). The role of inflammation in epilepsy. Nature Reviews Neurology, 7(1), 31–40. https://doi.org/10.1038/nrneurol.2010.178
Vezzani, A., Moneta, D., Richichi, C., Aliprandi, M., Burrows, S. J., Ravizza, T., Perego, C., & De Simoni, M. G. (2002). Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia, 43, 30–35. https://doi.org/10.1046/j.1528-1157.43.s.5.14.x
Waltl, I., Käufer, C., Bröer, S., Chhatbar, C., Ghita, L., Gerhauser, I., Anjum, M., Kalinke, U., & Löscher, W. (2018). Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis. Neurobiology of Disease, 110, 192–205. https://doi.org/10.1016/j.nbd.2017.12.001
Waltl, I., Käufer, C., Gerhauser, I., Chhatbar, C., Ghita, L., Kalinke, U., & Löscher, W. (2018). Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage. Brain, Behavior, and Immunity, 74, 186–204. https://doi.org/10.1016/j.bbi.2018.09.006
Wang, N., Mi, X., Gao, B., Gu, J., Wang, W., Zhang, Y., & Wang, X. (2015). Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neuroscience, 287, 144–156. https://doi.org/10.1016/j.neuroscience.2014.12.021
Weinberg, M. S., Blake, B. L., & McCown, T. J. (2013). Opposing actions of hippocampus TNFα receptors on limbic seizure susceptibility. Experimental Neurology, 247, 429–437. https://doi.org/10.1016/j.expneurol.2013.01.011
Wobbrock, J. O., Findlater, L., Gergle, D., & Higgins, J. J. (2011). The aligned rank transform for nonparametric factorial analyses using only anova procedures. In Proceedings of the SIGCHI conference on human factors in computing systems, pp. 143–146. Vancouver, BC, Canada: ACM. https://doi.org/10.1145/1978942.1978963.
Wu, W., Li, Y., Wei, Y., Bosco, D. B., Xie, M., Zhao, M.-G., Richardson, J. R., & Wu, L.-J. (2020). Microglial depletion aggravates the severity of acute and chronic seizures in mice. Brain, Behavior, and Immunity, 89, 245–255. https://doi.org/10.1016/j.bbi.2020.06.028
Wu, Z., Deshpande, T., Henning, L., Bedner, P., Seifert, G., & Steinhäuser, C. (2021). Cell death of hippocampal CA1 astrocytes during early epileptogenesis. Epilepsia, 62(7), 1569–1583. https://doi.org/10.1111/epi.16910
Wyatt-Johnson, S. K., Herr, S. A., & Brewster, A. L. (2017). Status epilepticus triggers time-dependent alterations in microglia abundance and morphological phenotypes in the hippocampus. Frontiers in Neurology, 8, 700. https://doi.org/10.3389/fneur.2017.00700
Yona, S., Kim, K.-W., Wolf, Y., Mildner, A., Varol, D., Breker, M., Strauss-Ayali, D., Viukov, S., Guilliams, M., Misharin, A., Hume, D. A., Perlman, H., Malissen, B., Zelzer, E., & Jung, S. (2013). Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity, 38(1), 79–91. https://doi.org/10.1016/j.immuni.2012.12.001
Zattoni, M., Mura, M. L., Deprez, F., Schwendener, R. A., Engelhardt, B., Frei, K., & Fritschy, J.-M. (2011). Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. Journal of Neuroscience, 31(11), 4037–4050. https://doi.org/10.1523/JNEUROSCI.6210-10.2011
Zhao, X., Liao, Y., Morgan, S., Mathur, R., Feustel, P., Mazurkiewicz, J., Qian, J., Chang, J., Mathern, G. W., Adamo, M. A., Ritaccio, A. L., Gruenthal, M., Zhu, X., & Huang, Y. (2018). Noninflammatory changes of microglia are sufficient to cause epilepsy. Cell Reports, 22(8), 2080–2093. https://doi.org/10.1016/j.celrep.2018.02.004