Abstracts

Rationale: Posttraumatic epilepsy (PTE) refers to the development of recurrent spontaneous seizures after a traumatic brain injury (TBI). The pathophysiology of PTE is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. Unfortunately, no treatments for PTE exists. Current models of PTE have focused on testing seizure susceptibility pharmacologically and injured animals were shown to be more susceptible to generalized seizures. While EEG studies have shown that animals with TBI can develop spontaneous seizures, no EEG biomarkers have been identified. In our studies, we aim to detect electrographic changes in the posttraumatic brain in wild type (WT) and in mice lacking the water channel protein aquaporin-4 (AQP4) to determine the role of AQP4 in the development of PTE. Methods: Adult male CD1 WT and AQP4 knockout (AQP4 KO) mice were used in our experiments and EEG analysis were assessed at various time points after injury (14, 30, 60, 90 days). Mice were subjected to a severe TBI in the right frontal cortex using a controlled cortical impact (CCI) injury device. Sham mice received craniotomy only. 10 days prior to the final time point, mice were implanted with an indwelling electrode in the ipsilateral hippocampus and then underwent continuous video-EEG recording for 1 wk to monitor for spontaneous seizures. At each final time point mice were subjected to in vivo electrical intrahippocampal stimulation for the quantitative assessment of electrographic seizure threshold (EST) and electrographic seizure duration (ESD).  Results: Spontaneous non-convulsive seizures were observed in injured mice and behavior associated with these electrographic seizures included immobility and excessive grooming. Sham mice did not display spontaneous seizures. No significant differences were observed in EST between TBI and sham groups in both genotypes. However, ESD was significantly higher in AQP4 KO mice compared to WT mice in both treatment groups (p<0.05). Power spectral density (PSD) analysis revealed significant increase in delta (p<0.001), theta (p<0.001), and alpha (p<0.05) power 14 d after TBI in WT mice, while a significant increase in delta (p<0.001) and theta (p<0.001) power was observed in AQP4 KO mice 14 d after TBI. Interestingly, wavelet analysis of spontaneous seizures revealed differences in power between WT and AQP4 KO mice at all time points. Conclusions: Our data suggest that AQP4 plays a role in epileptogenesis after TBI. Increase in EEG power 14 d after TBI suggests that mice may be more excitable at this time point after injury. Moreover, increased ESD after injury in AQP4 KO mice may relate to impaired K⁺ and water homeostasis. Histological studies for AQP4 and Kir4.1, astrocyte molecules known to modulate excitability, are also underway to correlate protein expression levels with electrographic changes. Funding: Not applicable