title: Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus.
abstract: Emerging data support roles for microRNA (miRNA) in the pathogenesis of various neurologic disorders including epilepsy. MicroRNA-134 (miR-134) is enriched in dendrites of hippocampal neurons, where it negatively regulates spine volume. Recent work identified upregulation of miR-134 in experimental and human epilepsy. Targeting miR-134 in vivo using antagomirs had potent anticonvulsant effects against kainic acid-induced seizures and was associated with a reduction in dendritic spine number. In the present study, we measured dendritic spine volume in mice injected with miR-134-targeting antagomirs and tested effects of the antagomirs on status epilepticus triggered by the cholinergic agonist pilocarpine. Morphometric analysis of over 6,400 dendritic spines in Lucifer yellow-injected CA3 pyramidal neurons revealed increased spine volume in mice given antagomirs compared to controls that received a scrambled sequence. Treatment of mice with miR-134 antagomirs did not alter performance in a behavioral test (novel object location). Status epilepticus induced by pilocarpine was associated with upregulation of miR-134 within the hippocampus of mice. Pretreatment of mice with miR-134 antagomirs reduced the proportion of animals that developed status epilepticus following pilocarpine and increased animal survival. In antagomir-treated mice that did develop status epilepticus, seizure onset was delayed and total seizure power was reduced. These studies provide in vivo evidence that miR-134 regulates spine volume in the hippocampus and validation of the seizure-suppressive effects of miR-134 antagomirs in a model with a different triggering mechanism, indicating broad conservation of anticonvulsant effects.
authors.affiliation: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.forename: Paula
authors.initials: P
authors.lastname: Merino-Serrais
authors.forename: Isabel
authors.initials: I
authors.lastname: Fernaud-Espinosa
authors.forename: Natalia
authors.initials: N
authors.lastname: Rodriguez-Alvarez
authors.forename: James
authors.initials: J
authors.lastname: Reynolds
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Reschke
authors.forename: Ronan M
authors.initials: RM
authors.lastname: Conroy
authors.forename: Ross C
authors.initials: RC
authors.lastname: McKiernan
authors.forename: Javier
authors.initials: J
authors.lastname: deFelipe
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000473:pathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009474:Neurons / Q000473:pathology*; D009841:Oligonucleotides / Q000627:therapeutic use; D010862:Pilocarpine / Q000633:toxicity; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D018709:Statistics, Nonparametric; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors
chemical_list: D035683:MicroRNAs; C551912:Mirn134 microRNA, mouse; D009841:Oligonucleotides; D010862:Pilocarpine