Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Gary P. Brennan, Deblina Dey, Yuncai Chen, Katelin P. Patterson, Eric J. Magnetta, Alicia M. Hall, Celine M. Dube, Yu-Tang Mei, Tallie Z. Baram
Insult-provoked transformation of neuronal networks into epileptic ones involves multiple mechanisms. Intervention studies have identified both dysregulated inflammatory pathways and NRSF-mediated repression of crucial neuronal genes as contributors to epileptogenesis. However, it remains unclear how epilepsy-provoking insults (e.g., prolonged seizures) induce both inflammation and NRSF and whether common mechanisms exist. We examined miR-124 as a candidate dual regulator of NRSF and inflammatory pathways. Status epilepticus (SE) led to reduced miR-124 expression via SIRT1—and, in turn, miR-124 repression—via C/EBPα upregulated NRSF. We tested whether augmenting miR-124 after SE would abort epileptogenesis by preventing inflammation and NRSF upregulation. SE-sustaining animals developed epilepsy, but supplementing miR-124 did not modify epileptogenesis. Examining this result further, we found that synthetic miR-124 not only effectively blocked NRSF upregulation and rescued NRSF target genes, but also augmented microglia activation and inflammatory cytokines. Thus, miR-124 attenuates epileptogenesis via NRSF while promoting epilepsy via inflammation.

Graphical abstract

Teaser

Brennan et al. find that miR-124 is involved in insult-induced epilepsy. They find that activation of SIRT1 represses miR124. This repression affects miR-124 targeting of NRSF; however, it may also act to reduce inflammation that contributes to epilepsy development. Thus, miR-124 has opposing roles in the development of epilepsy.


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