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Cell Rep. 2016 Mar 15;14(10):2402-12. doi: 10.1016/j.celrep.2016.02.042. Epub 2016 Mar 3.

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

Author information

1
Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
2
Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA.
3
Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
4
Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: tallie@uci.edu.

Abstract

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.

PMID:
26947066
PMCID:
PMC4794429
DOI:
10.1016/j.celrep.2016.02.042
[Indexed for MEDLINE]
Free PMC Article

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