Ccr2-KO leads to protection from hippocampal neurodegeneration in Theiler's virus model of epilepsy
C. Käufer1, C. Chhatbar2, S. Bröer1, I. Waltl1, I. Gerhauser3, U. Kalinke2, W. Löscher1
1Department of Pharmacology, University of Veterinary Medicine Hannover, Germany; 2Institute for Experimental Infection Research, TWINCORE, Hannover; 3Department of Pathology, University of Veterinary Medicine Hannover
Viral encephalitis is among the leading causes of seizures in humans worldwide and up to 20% of surviving encephalitis patients develop epilepsy. In a recently described model C57BL/6J (B6) mice developed acute and chronic seizures and hippocampal neurodegeneration after intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV). Recent data suggest that infiltrating monocytes play a key role in seizure generation in this model, which prompted us to further examine the role of monocytes and microglia in hippocampal pathology, and the development of acute and chronic seizures.
We infected B6 and Ccr2-KO mice, which show decreased accumulation of myeloid cells in CNS upon infection with TMEV and monitored for acute and chronic seizure development using continuous EEG-/video surveillance (90-98 dpi). On day 7 post infection (dpi) the hippocampi were histologically analyzed for neurodegeneration (NeuN, FJC) and presence of activated myeloid cells (Mac3, Iba1). Genetic labelling of microglia and flow cytometry was used to differentiate between microglia and infiltrating monocytes.
Although, compared to B6 mice, acute and chronic seizure occurrence did not differ in Ccr2-KO mice, they showed marked reduction of seizure severity, hippocampal neurodegeneration and acute hippocampal Mac3 staining. Flow cytometry showed a decrease in CD45highCD11b+ cells in the brain 7 dpi in Ccr2-KO mice compared to WT mice.
While elimination of Ccr2 did not alter the acute and chronic seizure incidence, it did result in the protection of hippocampal neurons. Enhanced survival of neurons could have a profound impact on post-encephalitis disease outcome, including the severity of epilepsy and associated comorbidities. Further experiments on the role of Ccr2-KO on virus-induced chronic seizures will provide insight into the role of Ccr2 and phagocytic cells in this model.
Supported by the N-RENNT network and by a bilateral project of the German Centre for Neurodegenerative Diseases and the Helmholtz Centre for Infection Research (CC and UK).