Abstracts

Rationale: Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality internationally. Approximately 20-50% of TBI patients develop post-traumatic epilepsy (PTE), which is typically more refractory in nature than other causes of epilepsy. Notably, since the onset of seizures in these cases typically does not occur for months or even years after injury, the progressive nature of this disorder offers a unique opportunity to examine mechanisms of epileptogenesis. In the 1990s, hippocampal atrophy was observed in human TBI and in a rodent model of TBI both ipsilateral and contralateral to the site of brain impact. Intriguingly, dentate hilar neurons appeared to be selectively vulnerable to progressive loss after injury and have been shown to be associated with a decrease in seizure threshold. Additionally, there is a persistent increase in blood brain barrier (BBB) permeability observed in humans and in rodent models of TBI. BBB breakdown is associated with increases in epileptogenic blood proteins such as thrombin, a serine protease present in the peripheral blood and the brain that is elevated after TBI. This pathway via Protease Activated Receptor 1(PAR1) signaling has been shown to alter glutamate transporter expression glutamate receptor signaling and neuroinflammation. Given the changes in thrombin signaling after TBI and the role of this pathway in neuroplasticity we hypothesize that it may play a role in epileptogenesis leading to PTE. Methods: To assess the molecular mechanism underlying PTE, we utilized the lateral fluid percussion injury model of traumatic brain injury and performed immunohistochemistry for proteins in the thrombin signaling pathway on slices of brain tissue from the hippocampus temporally after injury. Results: There are temporal changes in the PAR1 pathway leading to glutamate transporter expression. There was an early decrease in PAR1 immunoreactivity as well as an increase in neuroinflammation after TBI. Early glutamate transporter expression is unchanged.   Conclusions: These results suggest that there are early changes after TBI that may contribute to future neuroexcitability. Additionally, temporal changes in thrombin pathway signaling may contribute to epileptogenesis leading to PTE. Funding: This work was supported by R25 Grant NS065745.