Home > Publications Database > Ablation of CCL17-positive hippocampal neurons induces inflammation-dependent epilepsy. > print

001     276798
005     20250323000844.0
024 7 _ |a 10.1111/epi.18200
|2 doi
024 7 _ |a pmid:39607395
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024 7 _ |a pmc:PMC11827734
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024 7 _ |a 0013-9580
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024 7 _ |a 1528-1167
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024 7 _ |a altmetric:171522088
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037 _ _ |a DZNE-2025-00323
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Eberhard, Judith
|0 0009-0000-3445-6397
|b 0
245 _ _ |a Ablation of CCL17-positive hippocampal neurons induces inflammation-dependent epilepsy.
260 _ _ |a Oxford [u.a.]
|c 2025
|b Wiley-Blackwell
336 7 _ |a article
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a XPro1595
|2 Other
650 _ 7 |a astrogliosis
|2 Other
650 _ 7 |a diphtheria toxin
|2 Other
650 _ 7 |a microgliosis
|2 Other
650 _ 7 |a neurodegeneration
|2 Other
650 _ 7 |a Chemokine CCL17
|2 NLM Chemicals
650 _ 7 |a Ccl17 protein, mouse
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Epilepsy: pathology
|2 MeSH
650 _ 2 |a Epilepsy: drug therapy
|2 MeSH
650 _ 2 |a Hippocampus: pathology
|2 MeSH
650 _ 2 |a Hippocampus: drug effects
|2 MeSH
650 _ 2 |a Hippocampus: metabolism
|2 MeSH
650 _ 2 |a Neurons: drug effects
|2 MeSH
650 _ 2 |a Neurons: pathology
|2 MeSH
650 _ 2 |a Neurons: metabolism
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Chemokine CCL17: genetics
|2 MeSH
650 _ 2 |a Chemokine CCL17: metabolism
|2 MeSH
650 _ 2 |a Electroencephalography
|2 MeSH
650 _ 2 |a Cell Death: drug effects
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Microglia: drug effects
|2 MeSH
650 _ 2 |a Microglia: metabolism
|2 MeSH
650 _ 2 |a Microglia: pathology
|2 MeSH
650 _ 2 |a Pyramidal Cells: drug effects
|2 MeSH
650 _ 2 |a Pyramidal Cells: metabolism
|2 MeSH
650 _ 2 |a Pyramidal Cells: pathology
|2 MeSH
650 _ 2 |a Inflammation: pathology
|2 MeSH
650 _ 2 |a Inflammation: metabolism
|2 MeSH
700 1 _ |a Henning, Lukas
|0 0000-0003-4749-5162
|b 1
700 1 _ |a Fülle, Lorenz
|0 0000-0003-2087-2984
|b 2
700 1 _ |a Knöpper, Konrad
|0 0000-0003-2076-2160
|b 3
700 1 _ |a Böhringer, Jana
|b 4
700 1 _ |a Graelmann, Frederike
|0 P:(DE-2719)9000563
|b 5
700 1 _ |a Hänschke, Lea
|0 0000-0003-3964-6581
|b 6
700 1 _ |a Kenzler, Julia
|b 7
700 1 _ |a Brosseron, Frederic
|0 P:(DE-2719)2810593
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700 1 _ |a Heneka, Michael
|0 P:(DE-2719)2000008
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700 1 _ |a Domingos, Ana I
|0 0000-0002-7938-4814
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700 1 _ |a Eyerich, Stefanie
|0 0000-0002-1166-2355
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700 1 _ |a Lochner, Matthias
|0 0000-0002-7979-5613
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700 1 _ |a Weighardt, Heike
|0 0000-0002-3810-5890
|b 13
700 1 _ |a Bedner, Peter
|0 0000-0003-0090-7553
|b 14
700 1 _ |a Steinhäuser, Christian
|0 0000-0003-2579-8357
|b 15
700 1 _ |a Förster, Irmgard
|0 0000-0002-7644-5642
|b 16
773 _ _ |a 10.1111/epi.18200
|g Vol. 66, no. 2, p. 554 - 568
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|t Epilepsia
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856 4 _ |y OpenAccess
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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