Abstracts

Rationale: Post-traumatic epilepsy (PTE) represents 5% of all epilepsies and 10-20% of the acquired forms. There is a latent period between traumatic brain injury (TBI) and epilepsy onset that presents a unique window of opportunity for preventive treatments in high-risk patients, or for improving the disease course. The aim of this study was to generate a clinically relevant murine model of severe TBI suitable for biomarker and drug discovery.  Methods: Animal randomization and blinding procedures were applied. Severe TBI was performed in anesthetized 8 week-old CD1 male mice (n=28) by controlled cortical impact (CCI; 2 mm depth) over the left parieto-temporal cortex. TBI mice were longitudinally video-ECoG monitored, exposed to diffusion tensor imaging (DTI), 1H-magnetic resonance spectroscopy (MRS) in the thalamus ipsilateral to the injury, and tested for sensorimotor deficits (composite neuroscore and beam walk). At the end of video-ECoG recording all mice were sacrificed, and their brain were used for histopathological analysis. Sham animals were handled as TBI mice but were not exposed to CCI (n=14).  Results: TBI was associate with a 30% mortality (n=10) within the first month after TBI. PTE occurred in 55% of mice as determined by 3 weeks 24/7 video-ECoG recordings at 5 months post-TBI (number of spontaneous recurrent seizures (SRS)/day, 0.7 ± 0.2; SRS duration 50.1 ± 2.7 sec; n=10]. Consistently with clinical findings, mice with PTE (n=10) and mice with no SRS (n=8) showed similar degree of sensorimotor deficits up to 8 weeks post-TBI and a similar contusion volume at 6 months post-TBI compared to sham mice. White matter damage (DTI) was increased similarly in the two groups compared to sham mice. Notably, 1H-MRS at 2.5 months post-TBI revealed a 20% increase in glutamate and GLX (glutamate+glutamine) levels in the thalamus of PTE mice compared to sham mice, whereas no changes were detected in mice with no SRS. Conclusions: We characterized in-depth a PTE mouse model that recapitulates key features of the clinical condition. This model shows a PTE incidence and SRS frequency highly suitable for testing disease-modifying interventions, and for the discovery and validation of PTE biomarkers. 1H-MRS data highlight a deregulation of the glutamate-glutamine cycle which possibly contributes to PTE development.  Funding: No funding