MicroRNA-induced silencing in epilepsy: Opportunities and challenges for clinical application

Abstract

MicroRNAs are master regulators of gene expression. Single microRNAs influence multiple proteins within diverse molecular pathways and networks. Therefore, changes in levels or activity of microRNAs can have profound effects on cellular function. This makes dysregulated microRNA-induced silencing an attractive potential disease mechanism in complex disorders like epilepsy, where numerous cellular pathways and processes are affected simultaneously. Indeed, several years of research in rodent models have provided strong evidence that acute or recurrent seizures change microRNA expression and function. Moreover, altered microRNA expression has been observed in brain and blood from patients with various epilepsy disorders, such as tuberous sclerosis. MicroRNAs can be easily manipulated using sense or antisense oligonucleotides, opening up opportunities for therapeutic intervention. Here, we summarize studies using these techniques to identify microRNAs that modulate seizure susceptibility, describe protein targets mediating some of these effects, and discuss cellular pathways, for example neuroinflammation, that are controlled by epilepsy-associated microRNAs. We critically assess current gaps in knowledge regarding target- and cell-specificity of microRNAs that have to be addressed before clinical application as therapeutic targets or biomarkers. The recent progress in understanding microRNA function in epilepsy has generated strong momentum to encourage in-depth mechanistic studies to develop microRNA-targeted therapies. Developmental Dynamics 247:94-110, 2018. © 2017 Wiley Periodicals, Inc.

Keywords: RISC; miRNA; neuroinflammation; seizure; status epilepticus; therapy; tuberous sclerosis.

Figure 1. Simplified model depicting targets of candidate microRNAs and the associated epileptogenic pathways

Targets that have not been shown to be directly regulated by the respective microRNA are printed in italics. References are given in the main text.

Figure 2. Timeline for expression of known inflammatory miRNAs

Pro-inflammatory miRNAs are noted in red, while anti-inflammatory are given in blue. Some studies were performed on animal models (a), while others were performed in human tissues (h) obtained from surgical specimens of chronically seizing patients. Pre-treatment defines antagomirs that have demonstrated the ability to delay or suppress spontaneous recurrent seizures in rodent epilepsy models. References are given in the main text. Note that miR-146a mimics were also shown to suppress spontaneous recurrent seizures when given after the induction of seizures.