Epileptogenesis: Can the science of epigenetics give us answers?

Due to the complex progression of epilepsyand the multiple inherited and acquired factors that have influence on the onset and progression of this disease, developing cures for this disroder has proved to be challenging, with current treatment have focused on controlling seizure activity. Epigenetic mechanisms like DNA and histone modifications may contribute to epileptogenesis. Aberrant epigenetic patterns have already been identified in a number of central nervous system disorders like schizophrenia and Alzheimer disease, and this also includes epilepsy. It is still up to debate if the epigenetic changes are the cause or the result of many diseases. Here, we will discuss some recent findings suggesting that epileptogenesis alters the epigenetic landscape after seizures.

Seizure activity results in gene expression changes, including alterations in mRNA levels for GluR2 and bdnf (epileptogenesis-related genes). Following seizures in an animal model, histone acetyltransferases (HATs) mediated histone acetylation at the promoter regions of both genes, which could result in a higher expression of these genes. On the other hand, HDAC (histone deacetylase) inhibitors have been used as treatment for neurological disorders such as epilepsy. There has been evidence of hypermethylation  of the reelin promoter in association with temporal lobe epilepsy (TLE). Supporting this, there is increased expression of DNMT (DNA methyltransferase) in the neurons from the temporal neocortex of TLE patients. Histone methylation, like DNA methylation, may also play a role in epileptogenesis. The JARID1C histone demethylase is associated with X-linked mental retardation and in a minority of epilepsy patients. Also, as histone methylation is critical for memory formation, abnormal regulation of this methylation may lead to cogitive decline, which is associated with epilepsy. Some transcriptional activators recruit epigenetically related co-activators and repressors that influence chromatin restructuring. For example, the transciptional factor CREB and nuclear factor-kB are activated after a seizure and associate with HAT proteins to remodel chromatin. The transcription factor REST has also been implicated in the regulation of several epileptogenesis specific factors, like growth factors, neurotransmitter receptors, and ion channels. These finding suggest that there is a possibility of developing epigenetic based drug therapy. For example, VPA is a drug treatment used for epilepsy and was recently discovered to have HDAC inhibitory properties.

For more information, you can read the paper cited here:

Lubin, F. D. (2012). Epileptogenesis: can the science of epigenetics give us answers?. Epilepsy Currents, 12(3), 105-110.