RECENT DEVELOPMENTS: In the past 5 years, studies have found changes in
miRNA levels in the hippocampus of patients with
temporal lobe epilepsy and in neural tissues from animal models of
epilepsy. Early functional studies showed that silencing of brain-specific miR-134 using
antisense oligonucleotides (
antagomirs) had potent antiseizure effects in animal models, whereas genetic deletion of miR-128 produced fatal
epilepsy in mice. Levels of certain
miRNAs were also found to be altered in the blood of rodents after
seizures. In the past 18 months, functional studies have identified nine novel
miRNAs that appear to influence
seizures or hippocampal pathology. Their targets include
transcription factors,
neurotransmitter signalling components, and modulators of
neuroinflammation. New approaches to manipulate
miRNAs have been tested, including injection of mimics (agomirs) to enhance brain levels of
miRNAs. Altered
miRNA expression has also been reported in other types of
refractory epilepsy and our understanding of how
miRNA levels are controlled has grown, with studies on DNA methylation indicating epigenetic regulation. Biofluids (blood) of patients with
epilepsy have shown differences in quantity of circulating
miRNAs, implying diagnostic
biomarker potential. WHERE NEXT?: Recent functional studies need to be replicated to build a robust evidence base. The specific cell types in which
miRNAs execute their functions and their primary targets have to be identified, to fully explain the phenotypic effects of modulating
miRNAs. Delivery of large molecules such as antisense inhibitors or mimics to the brain poses a challenge, and the multi-targeting effects of
miRNAs create additional risks of unanticipated side effects. Potential genetic variation in
miRNAs should be explored as the basis for
disease susceptibility. The latest findings provide a rich source of new
miRNA targets, but substantial challenges remain before their role in the pathogenesis, diagnosis, and treatment of
epilepsy can be translated into clinical practice.