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@ARTICLE{Henning:165273,
      author       = {Henning, Lukas and Antony, Henrike and Breuer, Annika and
                      Müller, Julia and Seifert, Gerald and Audinat, Etienne and
                      Singh, Parmveer and Brosseron, Frederic and Heneka, Michael
                      T. and Steinhäuser, Christian and Bedner, Peter},
      title        = {{R}eactive microglia are the major source of tumor necrosis
                      factor alpha and contribute to astrocyte dysfunction and
                      acute seizures in experimental temporal lobe epilepsy},
      journal      = {Glia},
      volume       = {71},
      number       = {2},
      issn         = {0894-1491},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley-Liss},
      reportid     = {DZNE-2022-01566},
      pages        = {168 - 186},
      year         = {2023},
      note         = {CC BY-NC-ND:
                      https://creativecommons.org/licenses/by-nc-nd/4.0/},
      abstract     = {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.},
      keywords     = {Mice / Animals / Humans / Epilepsy, Temporal Lobe:
                      pathology / Astrocytes: pathology / Tumor Necrosis
                      Factor-alpha / Microglia: pathology / Hippocampus: pathology
                      / Seizures: pathology / Status Epilepticus: pathology /
                      Kainic Acid: toxicity / Disease Models, Animal / Mice,
                      Knockout / astrocyte (Other) / gap junction coupling (Other)
                      / hippocampal sclerosis (Other) / microglia (Other) /
                      temporal lobe epilepsy (Other) / tumor necrosis factor alpha
                      (Other) / Tumor Necrosis Factor-alpha (NLM Chemicals) /
                      Kainic Acid (NLM Chemicals)},
      cin          = {AG Heneka1 ; AG Heneka 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1011301},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36373840},
      doi          = {10.1002/glia.24265},
      url          = {https://pub.dzne.de/record/165273},
}