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@ARTICLE{Eberhard:276798,
      author       = {Eberhard, Judith and Henning, Lukas and Fülle, Lorenz and
                      Knöpper, Konrad and Böhringer, Jana and Graelmann,
                      Frederike and Hänschke, Lea and Kenzler, Julia and
                      Brosseron, Frederic and Heneka, Michael and Domingos, Ana I
                      and Eyerich, Stefanie and Lochner, Matthias and Weighardt,
                      Heike and Bedner, Peter and Steinhäuser, Christian and
                      Förster, Irmgard},
      title        = {{A}blation of {CCL}17-positive hippocampal neurons induces
                      inflammation-dependent epilepsy.},
      journal      = {Epilepsia},
      volume       = {66},
      number       = {2},
      issn         = {0013-9580},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2025-00323},
      pages        = {554 - 568},
      year         = {2025},
      abstract     = {Neuronal cell death and neuroinflammation are
                      characteristic features of epilepsy, but it remains unclear
                      whether neuronal cell death as such is causative for the
                      development of epileptic seizures. To test this hypothesis,
                      we established a novel mouse line permitting inducible
                      ablation of pyramidal neurons by inserting simian diphtheria
                      toxin (DT) receptor (DTR) cDNA into the Ccl17 locus. The
                      chemokine CCL17 is expressed in pyramidal CA1 neurons in
                      adult mice controlling microglial quiescence.Seizure
                      activity in CCL17-DTR mice was analyzed by
                      electroencephalographic recordings following treatment with
                      DT for 3 consecutive days. Neuroinflammation and neuronal
                      cell death were evaluated by (immuno)histochemistry.
                      Pharmacological inhibition of TNFR1 signaling was achieved
                      by treatment with XPro1595, a dominant-negative inhibitor of
                      soluble tumor necrosis factor.Neuronal cell death was
                      detectable 7 days (d7) after the first DT injection in
                      heterozygous CCL17-DTR mice. Spontaneous epileptic seizures
                      were observed in the vast majority of mice, often with an
                      initial peak at d6-9, followed by a period of reduced
                      activity and a gradual increase during the 1-month
                      observation period. Microglial reactivity was overt from d5
                      after DT administration not only in the CA1 region but also
                      in the CA2/CA3 area, shortly followed by astrogliosis.
                      Reactive microgliosis and astrogliosis persisted until d30
                      and, together with neuronal loss and stratum radiatum
                      shrinkage, reflected important features of human hippocampal
                      sclerosis. Granule cell dispersion was detectable only 3
                      months after DT treatment. Application of XPro1595
                      significantly reduced chronic seizure burden without
                      affecting the development of hippocampal sclerosis.In
                      conclusion, our data demonstrate that sterile pyramidal
                      neuronal death is sufficient to cause epilepsy in the
                      absence of other pathological processes. The CCL17-DTR mouse
                      line may thus be a valuable model for further mechanistic
                      studies on epilepsy and assessment of antiseizure
                      medication.},
      keywords     = {Animals / Mice / Epilepsy: pathology / Epilepsy: drug
                      therapy / Hippocampus: pathology / Hippocampus: drug effects
                      / Hippocampus: metabolism / Neurons: drug effects / Neurons:
                      pathology / Neurons: metabolism / Mice, Transgenic /
                      Chemokine CCL17: genetics / Chemokine CCL17: metabolism /
                      Electroencephalography / Cell Death: drug effects / Mice,
                      Inbred C57BL / Male / Disease Models, Animal / Microglia:
                      drug effects / Microglia: metabolism / Microglia: pathology
                      / Pyramidal Cells: drug effects / Pyramidal Cells:
                      metabolism / Pyramidal Cells: pathology / Inflammation:
                      pathology / Inflammation: metabolism / XPro1595 (Other) /
                      astrogliosis (Other) / diphtheria toxin (Other) /
                      microgliosis (Other) / neurodegeneration (Other) / Chemokine
                      CCL17 (NLM Chemicals) / Ccl17 protein, mouse (NLM
                      Chemicals)},
      cin          = {AG Heneka},
      ddc          = {610},
      cid          = {I:(DE-2719)1011303},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39607395},
      pmc          = {pmc:PMC11827734},
      doi          = {10.1111/epi.18200},
      url          = {https://pub.dzne.de/record/276798},
}