Abstract
Despite a large number of anti‐epileptic drugs on the market, many patients suffering from partial complex epilepsy with secondary generalizations (PCE) are refractory to current medications. Thus identification of new therapeutic targets is required. This work focused on two targets, Gαo and Gαi2. We hypothesized that increasing activity of these proteins would be protective from seizures as inhibition of these and related proteins by pertussis toxin enhances seizure susceptibility in a pilocarpine model. Mouse lines were created with increased activity of Gαo (Gαo RGSi) or Gαi2 (Gαi2 RGSi). Both mouse lines were exposed to a chemical kindling model with relevance to PCE using repeated injections of pentylenetetrazol (35mg/kg, i.p.) three times per week. Gαo +/RGSi mice have a faster onset to seizure on the C57Bl/6J background while Gαi2 +/RGSi mice have no change compared to littermate controls. The enhanced kindling in Gαo +/RGSi mutant mice is background dependent, whereby Gαo +/RGSi mice on the 129SvImJ background kindle no faster than their littermate controls. Furthermore, a 129SvImJ modifier locus that we previously identified on Chromosome 17 that reduces early lethality of Gαo +/RGSi mice also reduces the rate at which Gαo +/RGSi mice kindle on the C57Bl/6J background. (Supported by NIH R01 GM036592‐23 and a fellowship from the PhRMA Foundation)
Published Version
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