RESUMEN

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.

Asunto(s)

Redes Reguladoras de Genes , MicroARNs/metabolismo , Proteínas Represoras/metabolismo , Regiones no Traducidas 3'/genética , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Inmunoprecipitación de Cromatina , Citocinas/genética , Citocinas/metabolismo , Agonistas de Aminoácidos Excitadores/farmacología , Redes Reguladoras de Genes/efectos de los fármacos , Hipocampo/metabolismo , Ácido Kaínico/farmacología , Ratones , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Oligonucleótidos Antisentido/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Represoras/química , Proteínas Represoras/genética , Sirtuina 1/metabolismo , Estado Epiléptico/genética , Estado Epiléptico/patología