Abstracts

Rationale: The Project 2 of EpiBioS4Rx aims to identify new targets and antiepileptogenic therapies to prevent post-traumatic epilepsy (PTE), using the lateral fluid percussion injury (LFPI) model. Hyperphosphorylated tau (p-tau) has been found in many neurodegenerative processes but also in acquired epileptic disorders, such as PTE. In this study, we examined whether excessive p-tau is also a feature of the LFPI model in two different early time points after traumatic brain injury (TBI). Methods: Male 11-week old Sprague-Dawley rats were randomized into three different groups: naïve (n=6), sham (n=5/time point) and LFPI (n=5/time point). A 5mm craniotomy was performed in both sham and LFPI rats on the left parietal bone. To induce severe TBI, LFPI rats were subjected to a 3.2 (±0.1) atm pulse at the craniotomy. Sham and LFPI were euthanized at 2 or 7 days post-craniotomy, and naïve were age-matched. Perfused brains were used for immunohistochemistry assays of p-tau at Ser202/Thr205 (AT8 antibody) or Thr231 (AT180 antibody). Density of the staining was examined in the ipsi- and contralateral primary motor (M1), somatosensory (S2a, S2b) and granular insular (GI) cortices of individual AT8 or AT180 positive cell somata and background using ImageJ. Results were expressed as percentage of right cerebral cortex cell somata of the naïve stained in the same assay. Western blot studies on fresh brain tissue using similar antibodies are ongoing. Results: Significant increase in both somatic and diffuse background AT8 immunoreactivity (AT8-ir) was seen at 2-days post-LFPI, but not at 7-days. Specifically, the left GI had increased somatic AT8-ir compared to both controls and contralateral GI of the same LFPI rats. The left M1, S2a, and S2b regions also showed increased somatic AT8-ir compared to contralateral homotypic regions in LFPI rats, after 2 days. Shams showed increased AT8-ir at the left M1 region, 7 days post-craniotomy (p=0.01). Diffuse AT8-ir increase in the background was also observed 2 days post-LFPI compared to all other groups at S2a, S2b, and GI regions. Somatic AT180-ir was also increased at the left M1 region at 2 days post-craniotomy in both LFPI (p=0.01) and sham (p=0.04) in comparison with naïve rats. In addition, there were trends for increased AT180-ir in the background of the left S2a and S2b (p=0.06) than the right homotypic regions. Conclusions: Increased somatic and diffuse p-tau was seen in LFPI rats at 2 (but not at 7) days, post-LFPI with the following phosphorylation site-specific differences. Ser202/Thr205-p-tau expression was increased at the ipsilateral M1 (somatic) and S2a, S2b, and GI (somatic and diffuse) regions, 2 days post-LFPI. Thr231-p-tau was less specific and was increased in both LFPI and sham rats, at the M1 region ipsilaterally to the craniotomy, 2 days post-LFPI. These data support that p-tau might be a promising target for the design of pharmacotherapies with disease modifying and/or antiepileptogenic potential. Funding: Funded by NINDS U54 NS100064