title: Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks.
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.
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Brennan
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Deblina
authors.initials: D
authors.lastname: Dey
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Yuncai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Katelin P
authors.initials: KP
authors.lastname: Patterson
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Magnetta
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA; Department of Anatomy & Neurobiology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Dube
authors.affiliation: Department of Pediatrics, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Mei
authors.affiliation: 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.
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D053263:Gene Regulatory Networks / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D013226:Status Epilepticus / Q000235:genetics / Q000473:pathology; D000099229:RE1-Silencing Transcription Factor
chemical_list: D020413:3' Untranslated Regions; D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012097:Repressor Proteins; D056564:Sirtuin 1; D000099229:RE1-Silencing Transcription Factor