Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy

Gudenschwager-Basso, Erwin KristobalShandra, OleksiiVolanth, TroyPatel, Dipan C.Kelly, ColinBrowning, Jack L.Wei, XiaoranHarris, Elizabeth A.Mahmutovic, DzenisKaloss, Alexandra M.Correa, Fernanda GuilhaumeDecker, JeremyMaharathi, BiswajitRobel, StefanieSontheimer, HaraldVandeVord, Pamela J.Olsen, Michelle L.Theus, Michelle H.2023-04-272023-04-272023-04-25Gudenschwager-Basso, E.K.; Shandra, O.; Volanth, T.; Patel, D.C.; Kelly, C.; Browning, J.L.; Wei, X.; Harris, E.A.; Mahmutovic, D.; Kaloss, A.M.; Correa, F.G.; Decker, J.; Maharathi, B.; Robel, S.; Sontheimer, H.; VandeVord, P.J.; Olsen, M.L.; Theus, M.H. Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy. Cells 2023, 12, 1248.http://hdl.handle.net/10919/114827Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus—a structure that is highly susceptible to injury—has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2–4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE−), which may be associated with epileptogenesis. Results: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE− mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.application/pdfenCreative Commons Attribution 4.0 Internationaltraumatic brain injuryhippocampusgranular neuronsneuroblastsseizuresepilepsyPTEAtypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic EpilepsyArticle - Refereed2023-04-27Cellshttps://doi.org/10.3390/cells12091248