Ablation of CCL17-positive hippocampal neurons induces inflammation-dependent epilepsy.

Autor: Eberhard J; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany., Henning L; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.; Deutsche Forschungsgemeinschaft, Bonn, Germany., Fülle L; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.; Business Development Europe Research Services, WuXi Biologics, Leverkusen, Germany., Knöpper K; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.; Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA., Böhringer J; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany., Graelmann FJ; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany., Hänschke L; Molecular Developmental Biology, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany., Kenzler J; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.; Sanofi-Aventis Deutschland, Medical Operations General Medicines in Germany, Switzerland, Austria (GSA), Berlin, Germany., Brosseron F; German Center for Neurodegenerative Diseases, Bonn, Germany., Heneka MT; German Center for Neurodegenerative Diseases, Bonn, Germany.; Luxembourg Center for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg., Domingos AI; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK., Eyerich S; Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany.; ZAUM-Center of Allergy and Environment, Technical University and Helmholtz Center Munich, Munich, Germany., Lochner M; Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany.; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Weighardt H; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany., Bedner P; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany., Steinhäuser C; Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany., Förster I; Immunology & Environment, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2024 Nov 28. Date of Electronic Publication: 2024 Nov 28.
DOI: 10.1111/epi.18200
Abstrakt: Objective: 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.
Methods: 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.
Results: 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.
Significance: 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.
(© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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