How Soon is Soon Enough? Consideration of Timing and Disease Etiology for microRNAs in Epilepsy

Abstract

Recurrent spontaneous seizures in epilepsy cause a myriad of structural, circuit-related, and molecular modifications in the brain. The multifaceted molecular changes suggest that wide-reaching epigenetic mechanisms are altered in epilepsy. Indeed, it has been known for more than 15 years that a class of epigenetic regulators called microRNAs-short, noncoding RNAs that control the translation and stability of sometimes hundreds of mRNA targets-are dysregulated after seizures and in epilepsy in human patients and rodent models. Epilepsy-associated microRNAs regulate many different molecular contributors to epilepsy, including ion channels, neuroinflammatory modulators, and proteins critical for neuronal and synaptic structure. In recent years, it has become clear that microRNAs are important at every phase of epilepsy-from the onset of the first seizure to the latent phase and chronic epilepsy. In line with these findings, manipulation of a subset of microRNAs has been shown to alter seizure susceptibility, reduce epileptogenesis, and/or decrease the frequency of spontaneous recurrent seizures in animal models of epilepsy. These studies illustrate the promise of microRNAs as future therapeutic targets in epilepsy and show that specific microRNAs play different regulatory roles depending on the phase and type of epilepsy. In this concise review, we summarize recent findings of microRNAs in epilepsy, emphasizing novel approaches that advance the field. We discuss the insight on underlying mechanisms and disease etiology that can be drawn from these studies and highlight the importance of timing when developing microRNA-based therapeutic strategies.

Keywords: biomarker; epilepsy; epileptogenesis; microRNA; therapy.

Figure 1.

Effects of manipulating select microRNAs on seizure phenotypes in rodent models depending on the timing of intervention. Top: Acquired epilepsy can be divided into 3 phases: preinsult (left), latent period (middle), and chronic epilepsy (right). Bottom: microRNA effects on epilepsy phenotype (defined as seizure onset, seizure severity, and/or seizure frequency). MicroRNAs in Italics were genetically deleted or overexpressed, while regular fonts indicate the use of antagomirs or agomirs. Only select microRNAs tested preinsult are shown (based on availability of electroencephalogram (EEG) to confirm seizures, testing in multiple models). For a more complete overview of microRNAs in epilepsy, see previous comprehensive reviews.^,