The functions of repressor element 1-silencing transcription factor in models of epileptogenesis and post-ischemia

Abstract

Epilepsy is a debilitating neurological disorder characterised by recurrent seizures for which 30% of patients are refractory to current treatments. The genetic and molecular aetiologies behind epilepsy are under investigation with the goal of developing new epilepsy medications. The transcriptional repressor REST (Repressor Element 1-Silencing Transcription factor) is a focus of interest as it is consistently upregulated in epilepsy patients and following brain insult in animal models of epilepsy and ischemia. This review analyses data from different epilepsy models and discusses the contribution of REST to epileptogenesis. We propose that in healthy brains REST acts in a protective manner to homeostatically downregulate increases in excitability, to protect against seizure through downregulation of BDNF (Brain-Derived Neurotrophic Factor) and its receptor, TrkB (Tropomyosin receptor kinase B). However, in epilepsy patients and post-seizure, REST may increase to a larger degree, which allows downregulation of the glutamate receptor subunit GluR2. This leads to AMPA glutamate receptors lacking GluR2 subunits, which have increased permeability to Ca²⁺, causing excitotoxicity, cell death and seizure. This concept highlights therapeutic potential of REST modulation through gene therapy in epilepsy patients.

Keywords: BDNF; Epigenetics; Epilepsy; Potassium channel; Transcription.

Fig. 1

The differential contributions of REST in seizure and ischemia models in pyramidal neurons. REST has either an overall protective (blue) or pathological (red) contribution to the effects of kindling and 4-AP seizure models (left), or status epilepticus seizure models and ischemia models (right), respectively. An excitatory stimulus within the ‘normal’ range for neurons, such as kindling in vivo, or 4-AP in vitro, causes membrane depolarization and Ca²⁺ influx through NMDA receptors and voltage gated Ca²⁺ channels. The Ca²⁺ increase enhances expression of BDNF and increases activity of Sirt1. This leads to an increase in the transcription factor C/EBP which enhances expression of REST. REST represses expression of voltage gated Na²⁺ channels and BDNF. BDNF protein is secreted outside of the cell, where it binds to TrkB receptors, activating PLCγ. PLCγ recruitment by TrkB represses expression of KCC2 transporters, leading the cell to a state of hypersensitivity of cells to excitatory stimuli. This process is downregulated by REST-mediated repression, as is the expression of voltage gated Na²⁺ channels which contribute to action potential spiking. Therefore the actions of upregulated REST in this system lead to an overall homeostatic reduction of excitability towards normal levels. In contrast, status epilepticus or administration of chemoconvulsants such as kainate cause a greater excessive influx of Ca²⁺ to the cell, leading to a larger increase in REST levels. In addition to the downstream effects seen in normal levels of excitation (left of diagram), REST here is also able to repress HCN1 and the AMPA receptor subunit GluR2. The repression of GluR2 leads to an increase in AMPA receptors lacking the GluR2 subunit, which have increased permeability to Ca²⁺. This allows an excessively large Ca²⁺ influx, which is also triggered by status epilepticus. The excitotoxic death of nearby interneurons induced by Ca²⁺ influx leads to reduced GABAergic signalling to the pyramidal neuron. In combination with the excessive Ca²⁺ influx, this reduced inhibition is sufficient to trigger neuron death in ischemia models, and additional epileptiform activity in chemoconvulsant seizure models. Repression of HCN1 expression by REST also contributes to the epileptiform activity and neuron death triggered by kainate exposure