MicroRNAs have emerged as important regulators of the gene expression landscape in
temporal lobe epilepsy. The mechanisms that control
microRNA levels and influence target choice remain, however, poorly understood. RNA editing is a post-transcriptional mechanism mediated by the
adenosine acting on
RNA (ADAR) family of
proteins that introduces base modification that diversifies the gene expression landscape. RNA editing has been studied for the
mRNA landscape but the extent to which
microRNA editing occurs in human
temporal lobe epilepsy is unknown. Here, we used small
RNA-sequencing data to characterize the identity and extent of
microRNA editing in human
temporal lobe epilepsy brain samples. This detected low-to-high editing in over 40 of the identified
microRNAs. Among
microRNA exhibiting the highest editing was
miR-376a-3p, which was edited in the seed region and this was predicted to significantly change the target pool. The edited form was expressed at lower levels in human
temporal lobe epilepsy samples. We modelled the shift in editing levels of
miR-376a-3p in human-induced pluripotent stem cell-derived neurons. Reducing levels of the edited form of
miR-376a-3p using
antisense oligonucleotides resulted in extensive gene expression changes, including upregulation of mitochondrial and metabolism-associated pathways. Together, these results show that differential editing of
microRNAs may re-direct targeting and result in altered functions relevant to the pathophysiology of
temporal lobe epilepsy and perhaps other disorders of neuronal hyperexcitability.