Abstracts

Rationale:
One trigger for developing epilepsy is an infection of the central nervous system (CNS); there is a 20% risk of chronic seizure manifestation as a consequence of encephalitis. This underscores the need to study epileptogenesis following CNS infections more closely to develop effective treatments for at-risk patients. Neurogenesis, the generation of new nerve cells, is disrupted in traditional rodent epilepsy models, and contributes to hyperexcitability and cognitive impairment. Our hypothesis is that similarly virus-induced seizures cause dysfunctional neurogenesis, facilitating seizures and cognitive deficits. We assessed the impact of encephalitis-derived seizures on the stem cell niche and the maturation and development of new neurons during epileptogenesis, aiming to identify targets for modulating neurogenesis.




Methods:
The Theiler’s murine encephalomyelitis virus (TMEV) model is a translational mouse model that simulates infection-triggered acute and chronic seizures. An intracortical, unilateral injection of the Daniel’s Strain of Theilervirus induces seizures in 50-75% C57BL6 mice within the first week. Mice were observed for the occurrence of acute seizures twice daily. An additional group of mice was EEG-monitored 24/7. Mice were sacrificed at 3-, 7-, 14- and 28-days post infection (dpi). Histological analyses of overall dentate gyrus cell proliferation, neurogenesis, neurodegeneration, and inflammation were performed in order to characterize neurogenesis under infection and acute seizure conditions.




Results:
TMEV infection rapidly depleted immature neurons (DCX+), with mice experiencing seizures demonstrating a more pronounced reduction in neuronal progenitor cell density relative to the control group, and induced ectopic migration in surviving neuronal progenitors at 14 dpi. On the contrary, proliferating astrocyte numbers were significantly increased in 14 dpi TMEV infected animals. Ongoing long-term fate tracking of progenitor cells by BrdU labelling in 28 dpi animals will be presented at the meeting. Additionally, higher cell counts and activation state of microglia and astrocytes, as well as more severe neurodegeneration were observed in seizing mice at 7 dpi.




Conclusions:
Seizure insult is not incipiently diminishing hippocampal cell proliferation in the TMEV model but rather shifts proliferation towards gliogenesis, resulting in reduction of neurogenesis. Furthermore, immature neurons are depleted by infection and seizures. Precisely determining if neurogenesis recovers, as well as following the fate of affected cells will hopefully enable us to identify targets and treatment windows for modulating neurogenesis.




Funding:
This study is funded by a grant from the Else Kröner-Fresenius-Stiftung to Sonja Bröer (2022 EKEA.132).