Astrogliosis as the Driver for Posttraumatic Epilepsy
Abstract
Nearly half of all reported cases of acquired epilepsy are caused by traumatic brain injury (TBI), which are often the result of accidental, recreational, and combat-related injuries. These acquired forms of epilepsy are predominately in young adults. Biological factors underlying post-traumatic epilepsy (PTE), as well as predictors for individuals developing epilepsy, remain elusive. In addition, failure of the clinical trials to prevent spontaneous post-traumatic seizures using currently available anti-epileptic drugs indicates presence of other, yet unknown reason for epilepsy. Mounting evidence suggests mild repeated TBI contributes to PTE. The influence of TBI on seizures and any cumulative TBI insults needed to cross a particular threshold to cause epilepsy have not been investigated. Further, it is uncertain if blast waves produced by explosions can cause epilepsy. Importantly, the effects of gender on PTE development also require attention. Epilepsy is devastating to patients, as seizures are largely unresponsive to current anti-seizure medications. Seizures significantly impair independent living and cause progressive cognitive decline. Despite our awareness of the initiating events, prevention of PTE with antiepileptic drugs has been unsuccessful. To date, nearly all research has focused on a specific cell in the brain called a neuron. Most treatments exclusively address neuron dysfunction. Alternatively, another cell in the brain called an astrocyte is known to abnormally increase in number in response to destruction of nearby neurons from brain trauma. Astrocytes might also be implicated in TBI, although it is unclear as to how astrocytes contribute to the development of PTE. Currently, the PTE research field is limited to two experimental PTE models. In these models, PTE incidence is low and differences from animal to animal have interfered with the emergence of a concise picture detailing disease mechanisms and PTE predictors. In patients, the risk for developing PTE is highest with severe injury, yet still significantly increases after mild TBI and blast exposure, which may adversely affect military personnel. Despite recent recognition of mild TBI as a cause for neurological dysfunction, technical difficulties in recording electrical signals from the brains of animals over long periods of time and a significantly lower PTE incidence have prevented the development of effective animal models for mild or blast TBI studies with confirmed spontaneous seizures. Our group has shown spontaneous seizures occur 21 days after repetitive mild TBI in mice. This mouse model is used to mimic a sport concussion. New data using the proposed repeated blast model have shown spontaneous, unprovoked seizures in 25% of mice beginning only 3 days after injury. Seizures recurred and were accompanied by additional behavioral abnormalities. The scientific objective of this project is to capture and compare differences between blast TBI animals with seizure-confirmed PTEs and seizure-free blast TBI animals to provide a comprehensive and unbiased analysis of the biological response contributing to blast-related PTE. We will expand upon our confirmed spontaneous seizure results and focus on astrocytes to identify biomarkers and molecular targets for the development of novel therapeutic approaches for PTE. The goals of the proposed study are: (1) to establish seizure onset, incidence, frequency and EEG properties following blast exposure; (2) to define PTE-distinguishing features in astrocytes after blast exposure; and (3) to comparative assessment of blast-PTE data to database of an impact-TBI PTE model. The risk of blast-induced PTE is a rising concern for current and retired military personnel. Results from the proposed study will unravel the critical and currently unknown mechanism underlying blast-TBI PTE and aims to identify key biomarkers and pursuable drug targets to help effectively monitor and treat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810521
Entities
People
- Pamela VandeVord
Organizations
- United States Army
- Virginia Tech