Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Erwin Kristobal Gudenschwager-Basso
ORCID logo ,
Oleksii Shandra
ORCID logo ,
Troy Volanth
,
Dipankumar Patel
,
Colin Kelly
,
Jack L Browning
ORCID logo ,
Xiaoran Wei
,
Dzenis Mahmutovic
,
Alexandra M Kaloss
,
Fernanda Guilhaume Correa
ORCID logo ,
Jeremy Decker
,
Biswajit Maharathi
,
Stefanie Robel
,
Harald Sontheimer
,
Pamela J VandeVord
ORCID logo ,
Michelle L Olsen
,
Michelle H Theus
* ORCID logo
Version 1 : Received: 8 February 2023 / Approved: 13 February 2023 / Online: 13 February 2023 (02:24:00 CET)

A peer-reviewed article of this Preprint also exists.

Gudenschwager-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. Gudenschwager-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.

Abstract

Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under under investigation. The dentate gyrus, a structure highly susceptible to injury, and 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 non-biased 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 was performed to determine differential gene expression in PTE+ vs. PTE- that may comport with the epileptogenic process. 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. 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.

Keywords

Traumatic brain injury; hippocampus

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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