1. Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks.
- Author
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Brennan GP, Dey D, Chen Y, Patterson KP, Magnetta EJ, Hall AM, Dube CM, Mei YT, and Baram TZ
- Subjects
- 3' Untranslated Regions genetics, Animals, CCAAT-Enhancer-Binding Proteins metabolism, Chromatin Immunoprecipitation, Cytokines genetics, Cytokines metabolism, Excitatory Amino Acid Agonists pharmacology, Hippocampus metabolism, Kainic Acid pharmacology, Mice, MicroRNAs antagonists & inhibitors, MicroRNAs genetics, Oligonucleotides, Antisense metabolism, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Repressor Proteins chemistry, Repressor Proteins genetics, Sirtuin 1 metabolism, Status Epilepticus genetics, Status Epilepticus pathology, Gene Regulatory Networks drug effects, MicroRNAs metabolism, Repressor Proteins metabolism
- 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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