Abstracts

Rationale: Epileptogenic insults such as status epilepticus (SE) induce rapid changes in cellular properties caused by large scale changes in gene expression and regulation. Among the regulatory pathways triggered by epilepsy-inducing insults and might contribute to epileptogenesis, are the transcriptional repressor NRSF and the inflammatory cascade. Inhibiting NRSF activity following SE significantly ameliorated, but did not eliminate, the subsequent epilepsy (1). Efforts to block inflammation have also failed to prevent epilepsy (2) suggesting that targeting of single pathways may be insufficient to alter disease course. Therefore, identification of key molecules which regulate multiple epileptogenic pathways could lead to the development of effective anti-epileptogenic therapies. MicroRNAs are small non coding RNAs which post-transcriptionally regulate gene expression by targeting mRNA. Recent work suggested that mir-124 acts as a repressor of inflammation, and has been reported to regulate NRSF during neuronal maturation. Here we tested if mir-124 might play a dual role in epileptogenesis by regulating both NRSF and inflammation and investigated its therapeutic potential.Methods: SE was induced in adult rats by systemic KA. mRNA levels were quantified by qPCR. Protein levels were measured by w.blot. To test the effect of miR-124 treatment on epileptogenesis rats received miR-124 mimic infusion via ICV after SE and were monitored using 24h video-EEG for 60 days. To determine miR-124 mediated regulation of NRSF expression and inflammatory pathways, miR-124 mimics were infused via ICV, immediately after SE cessation.Results: SE robustly reduced hippocampal mir-124, and increased NRSF mRNA and protein levels as well as many pro-inflammatory cytokines. MiR-124 restitution failed to prevent epilepsy development. We explored why miR-124 had no effect on seizure development. MiR-124 restitution prevented seizure-induced NRSF expression and activity however, unexpectedly, miR-124 mimics exacerbated inflammation, indicating a dual counter-balancing role of miR-124 in epileptogenesis.Conclusions: MiR-124 plays a complex role in epileptogenesis. Reduced miR-124 is pro-epileptogenic leading to increased NRSF expression and activity. While reduced miR-124 is anti-epileptogenic because reduced miR-124 dampens the inflammatory response induced by epileptogenic insults. Although miR-124 restitution was unable to prevent epileptogenesis we have identified the regulatory mechanisms underlying aberrant NRSF activity during epileptogenesis and also revealed a more complex role for miR-124 in regulating inflammation.