Molecular and Cellular Basis of Spiking and Seizures in Neocortical Epilepsy

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Summary: Epilepsy is a disease of recurrent seizures that affects up to 1% of the world's population. At present time, we understand very little about how regions of the human brain become epileptic and produce seizures. We also have no medications that cure or prevent epilepsy from forming, a process known as epileptogenesis. Current medications can suppress seizures, but have not been shown to prevent or cure the disease, so that epileptic patients who stop taking their medications continue to have seizures. One approach that can lead to a permanent reduction in seizures is epilepsy surgery to remove focal regions of the brain where seizures start. Long term intracranial recordings that are often performed as part of these surgeries reveal extremely frequent epileptic discharges or 'spikes' often at or near regions of the brain where seizures start, suggesting that these 'interictal' (between seizures) spikes are highly associated with epileptic brain regions. In fact interictal spikes appear before seizures in some animal models of epileptogenesis. However, the exact relationship between interictal spiking and seizures is not known nor is it clear whether treatments that block seizures block spiking or vice versa. Here, we plan to extend our work that has taken an unbiased approach to identify new therapeutic targets for epilepsy based on high throughput genomic studies from precisely localized human neocortical regions from patients who have undergone epilepsy surgery. We will use data acquired from gene expression studies in human epileptic brain to identify genes and molecular pathways associated with interictal spiking and compare these to brain regions that produce seizures. We have also developed a novel computational approach to differentiate tissue regions where interictal spiking is generated versus where it spreads. The spatial organization of specific cell types, genes, and signaling intermediates will be mapped to specific laminar regions as well as to recently discovered >microlesions= in deeper cortical layers that are present only in high spiking regions. Finally, an in vivo animal model that separates interictal spiking from seizures will be used to test the specific functions of MAP Kinase signaling on interictal spiking and seizures as potential therapeutics for both epileptogenesis and established epilepsy.