Impact of targeted granule cell ablation on seizure frequencies in the epileptic mouse

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Postnatally-generated dentate granule cells born as early as 5 weeks prior to an epileptic insult (and those generated after the insult) have been shown to integrate aberrantly into the hippocampus. Many studies suggest these abnormalities are pro-epileptogenic; however a few studies suggest they may provide a more protective, homeostatic effect. We hypothesize that this cell population is pro-epileptogenic and contributes to the occurrence of spontaneous seizures. This study will directly test this hypothesis using a novel transgenic mouse approach which causes expression of the diphtheria toxin receptor in neural progenitor cells and their daughter cells. This lineage of postnatally-generated dentate granule cells is henceforth susceptible to diphtheria toxin-induced apoptosis. Using this methodology, I intend to express the diphtheria toxin receptor in postnatally-generated dentate granule cells born just before and after an epileptogenic insult (status epilepticus). Diphtheria toxin will be administered after the animals develop epilepsy to selectively ablate the abnormal cells. Aim 1 will assess the influence this cell population has upon epileptiform activity measurable through field potential recordings. Aim 2 will determine if this cell population affects the occurrence of spontaneous seizures. We predict that cell ablation therapy will cause a disease reversal, as manifest by fewer spontaneous seizures. This approach, therefore, allows for pre-clinical testing for a novel therapy which may potentially lead to the development of improved treatment options for individuals suffering from epilepsy.