Activity dependent gene expression in human neocortical epilepsy.

摘要

Epilepsy is a common and devastating neurological disorder that affects upto 1% of the world's population. The most common type of epilepsy by far are the partial epilepsies resulting from one or more regions of heightened electrical excitability capable of producing repeated depolarizations that can spread rapidly throughout the brain, resulting in generalized convulsions. The molecular mechanisms underlying the development and maintenance of these focal epileptic regions of the brain are not well-understood.; In this study, we have combined high throughput functional genomics techniques with focused analysis of electrophysiological data from long-term sub-dural recordings in patients with pharmacoresistant epilepsy to identify gene expression changes associated with epileptic activity. We have identified the persistent induction of a core group of genes and have observed a consistent activation of transcription factors CREB, c-fos, EGR1 and EGR2 at the epileptic foci. These genes are known to play an important role in synaptic reorganization in models of developmental plasticity, learning and memory. Similarly, they may be involved in modulating the synaptic machinery, thus contributing to the development and maintenance of aberrant epileptic circuits in the epileptic neocortex.; Quantitative electrophysiology revealed the expression of these genes was correlated with the interictal spike activity in the epileptic neocortex, and not seizure frequency. We hypothesize that interictal spikes may play an important role in modulating the expression of these transcription factors and maintaining the epileptic state. Our studies also reveal a regional decrease in the expression of neuronal glutamate transporters EAAT3 and EAAT4, at the epileptic foci compared to the non-epileptic comparison cortex. The regional decrease in glutamate transporters may lead to increased glutamate levels at the epileptic foci, thereby promoting hyperexcitabiIity.; This study represents a genomic approach towards identifying the molecular mechanisms underlying the development and maintenance of the epileptic foci. Focused high throughput analysis of gene expression profiles can be utilized to identify common pathways involved in neocortical epilepsy. These genes represent a valuable set of biomarkers and potential targets for therapeutic intervention in partial epilepsy.