Abstracts

Rationale: Epilepsy and Alzheimer's disease are the most common neurological disorders characterized by neuroinflammation, neurodegeneration, and seizures. Both Fyn and tau mediate neurodegeneration in Alzheimer's disease (AD). While genetic ablation of either tau or Fyn seems to be protective against seizures in AD and epilepsy models (PMID:20655099), the roles of both Fyn and tau in the early phase of epileptogenesis are not clear. Particularly, it is not known whether a combination of Fyn and tau reduction can exert a more profound neuroprotective effect relative to a single reduction. Here, we evaluate the effects of genetic deletion of Fyn and/or tau in the early phase of epileptogenesis. Methods: We examined three knockout genotypes: fyn^-/-, tau^-/-, and double knockout fyn^-/-/tau^-/-, and wild type (WT) control. Animals were randomized, grouped, and coded before inducing the status epilepticus (SE) with 40 mg/kg PTZ (i.p). Behavioral seizures were video-recorded and analyzed to determine the severity of SE. At 24h animals were euthanized, the brains were harvested for immunohistochemistry and Western blot. Results: Relative to WT, all knockout mice had reduced severity of SE and increased latency to the onset of convulsive seizures (= stage 3). Both tau^-/- and double knockout fyn^-/-/tau^-/- mice had the highest reduction in SE severity compared to the WT mice (n=7-10, p<0.001). However, the fyn^-/- mice (C57 x S129) showed higher mortality (due to hydrocephalus) than the other KO mice, with death occurring in <20 min of seizure induction. This is in contrast to the protective effect in another strain of fyn KO mice (C57 X Balb-c) suggesting the impact of genetic background on seizure threshold and mortality (PMID: 29197620). In all KO groups, brain immunohistochemistry showed a reduction in neurodegeneration and neuroinflammation, as detected by NeuN and FJB (n=4-6, p < 0.0001), and reactive gliosis (<0.0001). We also found increased expression of phospo-tau (AT8, Ser202/Thr205) in the hippocampus and entorhinal cortex (p = 0.0498) and a significant reduction in the parvalbumin-GABAergic interneurons (PVB) in the WT mice (p < 0.001). Interestingly, in all KO mice, the PVB neurons were protected from PTZ-induced SE (n). In the hippocampus, the levels of inwardly rectifying potassium (Kir 4.1) channels were significantly downregulated in the astrocytes of WT mice whereas in all KO groups, Kir4.1 levels were unaffected by PTZ (p = 0.0011). Conclusions: Our study reveals that Fyn and tau can both promote seizures, and possibly epileptogenesis. In the PTZ model, deleting Fyn and/or tau decreased seizures and protected neurons, especially the PVB positive neurons, prevented reactive gliosis, and restored Kir4.1 levels. Post-SE intervention studies of Fyn and/or Tau are required to confirm their potential as therapeutic targets for prevention or modification of epileptogenesis. Funding: Supported by the start-up funds to Dr. Thippeswamy, ISU, Iowa, USA.