Abstract
Epilepsy is the oldest known neurological disorder in humans and has been extensively studied
for decades. Nevertheless ~30% epilepsy patients remain refractory to pharmacological
intervention today. Limitations of animal models that are used in anti-epileptic drug screening,
and a lack of novel translatable therapeutic targets hamper progress in drug development. In the
following projects, we have attempted to address these obstacles. First, we have developed a
model for seizure kindling using inhaled chemo-convulsant flurothyl that can be rapidly
developed and is appropriate to use in research for epileptogenesis as well as screening for
potential disease modifying theories. Next, we have pharmacologically characterized Kv1.1 KO
mice to be potentially incorporated in the anti-epileptic drug development program as a model for
drug resistant epilepsy (DRE). We report that ~32% Kv1.1 KO mice are resistant to the first ASD
in addition to exhibiting multiple other risk factors observed in human DRE patients. Finally, we
have used Kv1.1 KO mice and other acute seizure models to evaluate ser273 phosphorylation of
PPARγ as a potential anti-seizure target. We find that seizures are closely associated with
increased ser273 phosphorylation of PPARγ. We also find dysregulation in gene transcription of
PPARγ regulated histone deacetylates (SIRT3), anti-oxidants (SOD1), and mitochondrial solute
carriers (FABP7 and SLC25a1). However, PPARγ modulators that block ser273 phosphorylation
in adipose tissue could not block this phosphorylation in the hippocampus, and ser273
phosphorylation did not seem to be associated with the gene set analyzed. In summary, we report
(a) a novel model for chronic epilepsy with potential to use in screening procedures and to study
epileptogenesis (b) that Kv1.1 KO mice are a potential model for drug resistant epilepsy (c) that
ser273 phosphorylation of PPARγ may be a potential target for anti-epilepsy therapy.