title: Brain inflammation, neurodegeneration and seizure development following picornavirus infection markedly differ among virus and mouse strains and substrains.
abstract: Infections, particularly those caused by viruses, are among the main causes of acquired epilepsy, but the mechanisms causing epileptogenesis are only poorly understood. As a consequence, no treatment exists for preventing epilepsy in patients at risk. Animal models are useful to study epileptogenesis after virus-induced encephalitis and how to interfere with this process, but most viruses that cause encephalitis in rodents are associated with high mortality, so that the processes leading to epilepsy cannot be investigated. Recently, intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) in C57BL/6 (B6) mice was reported to induce early seizures and epilepsy and it was proposed that the TMEV mouse model represents the first virus infection-driven animal model of epilepsy. In the present study, we characterized this model in two B6 substrains and seizure-resistant SJL/J mice by using three TMEV (sub)strains (BeAn-1, BeAn-2, DA). The idea behind this approach was to study what is and what is not necessary for development of acute and late seizures after brain infection in mice. Receiver operating characteristic (ROC) curve analysis was used to determine which virus-induced brain alterations are associated with seizure development. In B6 mice infected with different TMEV virus (sub)strains, the severity of hippocampal neurodegeneration, amount of MAC3-positive microglia/macrophages, and expression of the interferon-inducible antiviral effector ISG15 were almost perfect at discriminating seizing from non-seizing B6 mice, whereas T-lymphocyte brain infiltration was not found to be a crucial factor. However, intense microglia/macrophage activation and some hippocampal damage were also observed in SJL/J mice. Overall, the TMEV model provides a unique platform to study virus and host factors in ictogenesis and epileptogenesis.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bröer
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hanover, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Käufer
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Haist
authors.affiliation: Center for Systems Neuroscience, Hanover, Germany; Department of Pathology, University of Veterinary Medicine, Germany.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Veterinary Medicine, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Gerhauser
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hanover, Germany.
authors.forename: Muneeb
authors.initials: M
authors.lastname: Anjum
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hanover, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.affiliation: Center for Systems Neuroscience, Hanover, Germany; Department of Pathology, University of Veterinary Medicine, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hanover, Germany. Electronic address: wolfgang.loescher@tiho-hannover.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000818:Animals; D001835:Body Weight; D004569:Electroencephalography; D018792:Encephalitis, Viral / Q000209:etiology / Q000473:pathology* / Q000821:virology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000473:pathology* / Q000821:virology; D010850:Picornaviridae Infections / Q000150:complications / Q000473:pathology*; D012640:Seizures / Q000209:etiology / Q000473:pathology*; D013045:Species Specificity; D013601:T-Lymphocytes / Q000473:pathology; D017945:Theilovirus / Q000235:genetics*
keywords: Encephalitis; Epileptogenesis; Hippocampal damage; ISG15; Infection; Interferon; Macrophages; Microglia; Seizures