Minimal Traumatic Brain Injury in Mice: Protease-Activated Receptor 1 and Thrombin-Related Changes

Minimal traumatic brain injury (mTBI) is partially defined by the existence of retrograde amnesia and is associated with microscopic bleeds containing activated coagulation factors. In a previous study, we have found that mTBI immediately releases thrombin-like activity in the brain, which induces amnesia by activating protease-activated receptor 1 (PAR-1) and blocking long-term potentiation (LTP). In the present study, we assessed the effects of mTBI on thrombin and PAR-1 levels in the brain using the same model. After the immediate elevation, thrombin activity returned to baseline 1h post-trauma and increased again 72h later (42% relative to control; p<0.005). These changes were associated with a significant increase in PAR-1 levels 24 (17%; p<0.05) and 72h (20%; p<0.05) post-trauma. Interestingly, the late elevation in thrombin-like activity was also associated with elevation of the major central nervous system thrombin inhibitor, protease nexin-1, 72h post-mTBI (10%; p<0.005). When thrombin was injected into brain ventricles, an increased sensitivity to seizure-like activity was detected at 72h post-mTBI. The results are compatible with astrocyte activation post-mTBI resulting in increased thrombin secretion, PAR-1 expression, and seizure sensitivity.