Abstracts

Summary: Epileptogenesis, the process leading to epilepsy, can be triggered by a brain insult such as brain trauma, status epilepticus or long febrile seizures. The initial insult produces complex alterations in the neuronal circuitry. These include down- and up-regulation of hundreds of genes, that are often long-lasting. Changes in gene expression could thus play a central role in the construction and maintenance of epileptogenic networks. This workshop focuses on the mechanisms by which epileptogenic insults provoke enduring changes in gene expression. Interfering with these mechanisms may be disease-modifying. Regulation of chromatin structure is a principle means of controlling gene expression in eukaryotes. The transcriptional repressor NRSF/REST controls many genes in the central nervous system involved in plasticity and disease, via chromatin structure modification. NRSF can potentially alter the expression of ~1800 genes that possess the cognate NRSE sequence. Dr. Baram will discuss the role of the NRSF/REST in epileptogenesis triggered by status epilepticus. She will focus on epigenetic effects of this repressor, on the emerging minimal set of epileptogenic genes , and on the use of NRSF/REST as a molecular target for aborting epileptogenesis. If NRSF/REST is central to epileptogenesis, its actions should be model-independent. Dr. Dingledine will present findings obtained using an epilepsy microarray consortium formed to identify model-independent changes in gene expression in dentate gyrus granule cells following three types of status epilepticus that lead to epileptogenesis. Differentially-expressed genes were highly enriched in NRSF/REST targets, pointing to a broad role for the REST/NRSE system in driving transcriptional responses to epileptogenesis. Importantly, the NRSF/REST gene itself is also regulated. Alternative splicing occurs after seizures, resulting in a truncated altered-function variant of NRSF termed REST4. Dr. Roopra will describe the mechanisms by which REST splicing is controlled and how this effect impacts neuronal gene expression.