Abstracts

Neural circuits undergo a diverse variety of long-term structural and functional alterations in response to pathological insults and repeated seizures. Insights into how injury and seizures induce alterations in neural circuits are of interest for understanding epileptogenesis and the consequences of seizures, and may provide opportunities for therapeutic intervention in these processes. Long-term alterations in neural circuits induced during epileptogenesis and seizures include neurogenesis, neuronal death, gliosis, axon sprouting, and modifications of membrane receptors and signaling pathways influencing cellular functions. These long-term alterations require long-term changes in gene expression patterns. Despite intensive research into seizure-induced immediate early gene (IEG) expression, very little is known about how changes in IEG expression initiate and regulate cascades of gene expression changes underlying long-term structural and functional reorganization of epileptic neural circuits. It is now apparent that in addition to the direct effects of IEGs on promoters, gene expression is powerfully controlled by modifications of chromatin structure through posttranslational acetylation and methylation of histones. While these mechanisms for regulation of gene expression are increasingly appreciated as basic aspects of molecular and cellular biology, the potential role of histone modification in seizure-induced gene expression has not been addressed
Immunoprecipitations were performed on extracts from cell lines, control and kainate treated adult rat brain extracts. Chromatin precipitations were performed on the same protein samples.
We have demonstrate that a seizure-induced transcription factor, neuron restrictive silencing factor (NRSF), interacts with a chromatin modifying methylase enzyme. This interaction potentially establishes long term, stable alterations in gene expression patterns that could regulate long-term gene expression underlying neural circuit alterations induced by seizures through the epigenetic mechanism of methylation of chromatin.We provide evidence for a direct interaction between the IEG NRSF and histone methylases. We also show that neuronal genes e.g.BDNF, the sodium channel NaV1.2 and Muscarinic Receptor Type 4 are associated with methylated histones in vivo and discuss stable alterations that occur in the methylation status of chromatin after seizure.
We propose that transient increases in NRSF levels after seizure activate permanent posttranslational modifications of chromatin through histone methylation to influence subsequent seizure-induced gene expression patterns and contribute to important functional consequences of repeated seizures through the epigenetic mechanism of chromatin modification
[Supported by: Department of Neurology, University of Wisconsin-Madison]