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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Chromatin Immunoprecipitation
  • Cytokines / genetics
  • Cytokines / metabolism
  • Excitatory Amino Acid Agonists / pharmacology
  • Gene Regulatory Networks* / drug effects
  • Hippocampus / metabolism
  • Kainic Acid / pharmacology
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oligonucleotides, Antisense / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sirtuin 1 / metabolism
  • Status Epilepticus / genetics
  • Status Epilepticus / pathology


  • 3' Untranslated Regions
  • CCAAT-Enhancer-Binding Proteins
  • Cytokines
  • Excitatory Amino Acid Agonists
  • MicroRNAs
  • Oligonucleotides, Antisense
  • RE1-silencing transcription factor
  • RNA, Messenger
  • Repressor Proteins
  • Sirtuin 1
  • Kainic Acid