A systems approach delivers a functional microRNA catalog and expanded targets for seizure suppression in temporal lobe epilepsy

MicroRNAs (miRNAs) are short noncoding RNAs that shape the gene expression landscape, including during the pathogenesis of temporal lobe epilepsy (TLE). In order to provide a full catalog of the miRNA changes that happen during experimental TLE, we sequenced Argonaute 2-loaded miRNAs in the hippocampus of three different animal models at regular intervals between the time of the initial precipitating insult to the establishment of spontaneous recurrent seizures. The commonly upregulated miRNAs were selected for a functional in vivo screen using oligonucleotide inhibitors. This revealed anti-seizure phenotypes upon inhibition of miR-10a-5p, miR-21-5p and miR-142-5p as well as neuroprotection-only effects for inhibition of miR-27a-3p and miR-431-5p. Pathway enrichment analysis on predicted and validated targets of these miRNAs indicated a role for TGFß signaling in a shared seizure-modifying mechanism. Together, these results identify functional miRNAs in the hippocampus and a pipeline of new targets for seizure control in epilepsy. Overall design: small RNA sequencing of Ago2-loaded miRNAs from three different rodent models across all phases of epilepsy development, two in mouse one in rat. Each model is sequenced in timepoints during epileptogenesis and at chronic phase. Each group is in triplicate.