Molecular plasticity in epilepsy and epileptogenesis: Emerging therapeutic targets from new insight into basic mechanisms


Our understanding of mechanisms underlying epilepsy and epileptiform activities has expanded dramatically within the last decade. For years, the focus of our basic research had been on the processes involved in neuronal excitation and synaptic inhibition, and that focus translated rather directly into an exploration of treatment strategies that targeted sodium channel function and GABAA receptor function. Although those targets remain a key component of the modern search for better therapies, investigators have also begun to consider other pathways and mechanisms. Indeed, as we have gained a more sophisticated understanding of how genetic mechanisms are “expressed,” we have become aware that there are a myriad of molecular pathways that influence if and how a particular gene product is generated or modulated, and how this modulation translates into alterations in the excitability of neural networks.

This Epilepsia supplement focuses on some of those molecular pathways and gene expression mechanisms.

Why should we, as editors of a research journal with a primarily clinical emphasis, publish articles that deal with such esoteric material? Why should you, as epileptologists, bother with reviews of such basic cellular mechanisms? We feel strongly that insight into these mechanistic pathways not only provides a deeper understanding of the processes by which excitability and epileptogenicity may be controlled, but also may lead to a large number of targets for novel treatments. In particular, given the current emphasis on “epileptogenesis”—the process(es) by which a “normal” brain can become abnormally excitable and chronically epileptic—these pathways and mechanisms offer potential new treatment strategies that may block or curtail epileptogenesis, or even provide “cures” for the epileptic brain.

One such set of pathways/mechanisms has been subsumed under the term “epigenetics.” Epigenetics involves regulatory processes that control and modify gene stability, plasticity, and expression, by modifying chromatin structure. Roopra et al. discuss a number of epigenetic mechanisms, focusing particularly on REST control of gene transcription and MeCP2 regulation of BDNF expression. Kobow and Blümcke review DNA methylation processes, describing how active DNA methylation may contribute to “molecular memory.”

Following the field’s long-standing focus on excitability and its current preoccupation with channelopathies, we offer two articles (Vacher and Trimmer; Poolos and Johnston) that deal with voltage-gated channels—what they are, where and how they are inserted into the cell membrane, and how their regulation influences general cell excitability. A review of synaptic activities (Cassilas-Espinosa et al.) introduces us to the complexity of synaptic transmission, focusing on glutamatergic excitatory processes and highlighting the multiple sites at which regulation and modulation might occur.

Finally, consistent with the emphasis of epilepsy research on inhibitory control of excitability, subsequent articles focus on regulation of receptor expression and modulation, particularly of GABAA receptor proteins. These reviews take us from the level of mRNA quality control (Macdonald and Kang) through pathways that regulate receptor expression (Grabenstatter et al.) to processes that modulate receptor function (Deeb et al.; Ferando and Mody).

We recognize that not every epilepsy clinician—and, indeed, not every epilepsy basic scientist—may feel compelled to incorporate the details of these control mechanisms into his/her understanding of epileptogenicity. We suggest, however, that a familiarity with these emerging areas of research is essential for the modern epileptologist. It is from this level of analysis that future treatment approaches are likely to develop. We hope, therefore, that this special issue finds a place on your desk or bookshelf.


The author has no conflicts of interest to disclose. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.