Temporal profile of pathological changes and gene regulation in a kainic acid induced Fischer 344 rat model of mesial temporal lobe epilepsy
Abstract
Mesial temporal lobe epilepsy (MTLE), one of the most common types of epilepsies, is characterized by seizure generation from the mesial temporal lobe. One of the leading hypotheses in epilepsy research is that aberrant mossy fiber (MF) sprouting in MTLE leads to spontaneous motor seizure generation. The present study was designed to evaluate this hypothesis in Fischer 344 rats following subcutaneous administration of KA and to identify biomarkers of degeneration and regeneration, especially long term gene regulation changes relative to histopathological changes. ^ An important finding in this model was the development of aberrant MF sprouting before induction of spontaneous motor seizures and subsequently decreasing prominence of aberrant MF sprouting concurrent with decreased spontaneous seizure incidence. The array data demonstrated temporal regulation of a number of genes/pathways pertaining to neuronal plasticity (RhoA, Rac1, Cdc42, BDNF, and Trk), neurodegeneration/protection (Caspase3, Bax, Cytochrome c, Smac/Diablo and Cox2), and inflammation/immuneresponse (TNF-α) after KA treatment. Notably, within the axon guidance signaling pathway, the majority of genes showed upregulation from Days 3 to 28 which correlated with the aberrant MF sprouting observed from Day 6. ^ In a related study in order to evaluate the utility of C-tau detection in CSF as a biomarker of neurodegeneration following KA administration, a technique was successfully developed to effectively collect CSF. These samples were used to evaluate c-Tau using an ELISA assay. Since ELISA assays conducted on CSF samples drawn at different time points following KA administration were negative, it was concluded that C-tau detection in CSF was not useful as a biomarker of neurodegeneration in the currently used MTLE model design. However, further studies are warranted to investigate the utility of this method to detect neurodegeneration in rat models using higher doses of KA. ^ This study provides a comprehensive view of long term gene regulation relative to histopathological lesions and strongly supports the role of aberrant MF sprouting in seizure generation. The immense data generated from our study provides a basis for future research to investigate the role of selected genes in pathogenesis of MTLE using knockout/knockdown approaches.^
Degree
Ph.D.
Advisors
Paul W. Snyder, Purdue University.
Subject Area
Biology, Neuroscience
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