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Anatomical Basis of Epileptogenesis in a Mouse Model of Traumatic Brain Injury
Author(s) -
Golub Victoria,
Reddy Samba
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04587
Subject(s) - epileptogenesis , astrogliosis , neuroscience , traumatic brain injury , neun , neuroinflammation , neurodegeneration , gliosis , hippocampus , medicine , neurogenesis , hippocampal formation , entorhinal cortex , pathology , epilepsy , psychology , central nervous system , disease , immunohistochemistry , psychiatry
Post‐traumatic epilepsy (PTE) is characterized by progressive spontaneous recurrent seizures (SRS) following traumatic brain injury (TBI). PTE is poorly controlled by current medications and the molecular pathophysiology of PTE is unclear. A critical step for preventing PTE is to determine a key pathway that drives disease progression during the “latent period” after TBI, termed epileptogenesis. The potential mechanisms of underlying post‐traumatic epileptogenesis include neuroinflammation, degeneration of neuronal cells, and alterations in the hippocampal neurogenesis and mossy fiber sprouting. In this study, we sought to demonstrate a causal anatomical relationship between neuroinflammation and/or neurodegeneration and the onset of PTE in mice. TBI was induced in mice by a controlled‐cortical impact paradigm and were then monitored by video‐EEG recording for 120 days with a deep electrode placed within the contralateral hippocampus. At days 1, 3, 7, 30, 60, 120 post‐TBI, brains were fixed for immunohistochemistry and analyzed for principal neurons (NeuN+), interneurons (PV+), astrogliosis (GFAP+), microgliosis (IBA1+), and neurogenesis (DCX). Alterations in hippocampal and hemispheric architecture were visualized with quantitative analysis. Pronounced atrophy was evident within the ipsilateral hemisphere in the form of large lesions which extended from the cortex to the hippocampus by 120 days. In the contralateral hippocampus, inflammatory markers of microgliosis and astrogliosis reached peak levels within the first week before steadily declining throughout the 120‐day observation period. In contrast, neurodegeneration of NeuN+ cells and PV+ interneurons was not evident at these early stages, but cell loss became unmistakable starting 30 days post‐TBI. By this point, nearly 30% of PV+ interneurons were lost, with the dentate gyrus serving as the greatest region of cell loss (~40% loss). These studies were repeated using a moderate 1mm injury to emphasize the relationship between injury severity and neurodegeneration. Our findings are reminiscent of preferential loss of inhibitory interneurons in epilepsy patients and suggest that early neuroinflammation may catapult neurodegeneration within the damaged areas, which appears to be a critical mechanism for the onset of epileptogenesis. Specifically, progressive loss of PV+ GABAergic interneurons within the dentate gyrus correlates with progression of SRS from 30 to 60 days, coinciding with the onset of SRS at 39 days post‐TBI. Support or Funding Information **Funded by DOD Award #W81XWH‐16‐1‐0660**