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. Current models of PTE have focused on testing seizure susceptibility pharmacologically and injured animals were shown to be more susceptible to generalized seizures. Imaging studies, while limited, have not identified a correlation between trauma and seizure susceptibility. In our studies, we aim to detect optical and electrographic changes in the posttraumatic brain in wildtype (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 KO mice were used in our experiments and EEG and optical analysis were assessed at various time points after injury. At day 0, animals were subjected to optical coherence tomography imaging (OCT) and a severe TBI using a controlled cortical impact injury device. Sham animals received craniotomy only. 10 days before the final time point, animals underwent the final OCT imaging and were implanted with an indwelling electrode in the ipsilateral hippocampus. Animals then underwent continuous video-EEG recording for 1 wk to monitor for spontaneous seizures. Mice were subjected to in vivo electrical intrahippocampal stimulation at the final time point (30, 60, and 90 d post TBI) for the quantitative assessment of electrographic seizure threshold (EST) and electrographic seizure duration (ESD). EST was recorded when a hippocampal afterdischarge (seizure) of at least 5 s was observed. Changes in optical attenuation coefficient (μ) in the gray and white matter were analyzed from OCT data.  Results: Spontaneous non-convulsive seizures was observed in injured animals. Sham animals did not display spontaneous seizures. No significant differences were observed in EST in either WT or AQP4 KO mice in sham or injured animals. ESD was significantly higher in WT mice than sham mice at 60 d post TBI (p <0.05) and in AQP4 KO mice compared with WT mice at 30 and 90 d post TBI (p<0.01 and p<0.001, respectively). OCT imaging revealed significant differences in μ in both the gray and white matter after injury (p<0.05). Conclusions: A significant increase in ESD was observed in WT mice 60 d post TBI suggesting a possible network enhancement towards excitability at this time. AQP4 KO mice exhibited a significant increase in ESD compared to WT mice after TBI suggesting a crucial role of AQP4 in water homeostasis in its contribution to the development of epilepsy after TBI. Moreover, significant changes in OCT-derived μ was observed in both gray and white matter which could potentially be related to edema and axonal damage. Our data suggest that AQP4 deletion plays a critical role in the development of PTE, particularly by increasing seizure duration after TBI. Further studies are underway to define the regulation and role of AQP4 in PTE after TBI. Funding: N/A