Thomas L. Beaumont, Ph.D. - US grants

DESCRIPTION (provided by applicant): Epilepsy is a common neurological disorder of spontaneous brain excitation that effects up to 1.0% of the population. It results in uncontrolled loss of normal function that can spread rapidly and evolve into a generalized convulsion. While mutations in genes involved in modulating neuronal excitability have been identified for a small proportion of patients with inherited epilepsy, the majority of patients do not possess such mutations, but instead have focal brain regions that initiate seizures. Exactly what makes such areas of human neocortex epileptic remains elusive, and it is also unclear what role ongoing epileptiform activity plays in potentiating this state. It is likely that activity dependent signaling pathways regulate gene expression changes which lead to changes in neuronal connectivity and excitability. We have recently shown the activation of pathways inducing EGR and AP1 transcription factors at regions of seizure onset. These pathways could promote the epileptic state through alterations in synaptic efficacy and plasticity. We hypothesize that regions of seizure spread represent regions of "early" epileptogenesis and have gene expression changes distinct from regions of seizure onset which represent "late" epileptogenesis. In this proposal, we will use subdural recording electrodes to map human neocortical epileptic foci in patients with medically intractable seizures, and measure differential gene expression at these foci and at regions of early seizure spread using oligonucleotide microarrays. The expression level of key plasticity-associated genes will be confirmed and their cellular localization determined. Understanding activity-dependent gene expression and the cell types involved will provide new insights into human epileptogenesis that will aid in clinical management and offer new therapeutic avenues for patients with epilepsy.