UC Riverside

Posttraumatic epilepsy (PTE) is a long-term negative consequence of traumatic brain injury (TBI) in which recurrent spontaneous seizures occur after the initial head injury. PTE develops over an undefined period where circuitry reorganization in the brain causes permanent hyperexcitability. Unfortunately, current existing antiepileptogenic drugs (AEDs) have all failed at treating PTE, and thus, there is a critical need to identify biomarkers of PTE to ultimately develop new therapeutic strategies. The pathophysiology by which trauma leads to spontaneous seizures is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. Current animal studies of PTE are limited and comprehensive in vivo electrophysiological approaches remain absent. In the present study, I aimed to identify optical and electrographic biomarkers of PTE with correlation to hippocampal histopathology at 14, 30, 60, and 90 days post injury (dpi). Here, adult male CD1 wildtype (WT) and aquaporin-4 knockout (AQP4 KO) mice were subjected to a moderate-severe TBI in the right frontal cortex using the well-established controlled cortical impact (CCI) injury model. Additionally, mice underwent optical coherence tomography (OCT) imaging, in vivo video-electroencephalographic (vEEG) recordings, and immunohistochemistry and Western blot analysis for the key epileptogenic astrocytic channels AQP4 and Kir4.1. The main findings from these studies are: 1) successful implementation of CCI-based PTE in mice with chronic vEEG generated, for the first time,17% and 27% of WT and AQP4 KO mice with PTE, respectively (the highest yield of PTE reported); 2) AQP4 KO mice had a greater incidence of spontaneous seizures and PTE compared with WT mice; 3) AQP4 KO mice had longer spontaneous seizure duration compared with WT mice; 4) EEG power patterns are different between mice with and without PTE; and 5) AQP4, but not Kir4.1, is significantly upregulated in the frontal cortex and hippocampus of mice with PTE. Collectively, these findings identified specific PTE EEG phenotypes that may be modulated by AQP4 and carry significant implications for epileptogenesis after TBI which may serve as the first steps to developing surrogate biomarkers for PTE.