Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus.

Brain structure & function 2015 Jul

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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.

Citation

Eva M Jimenez-Mateos, Tobias Engel, Paula Merino-Serrais, Isabel Fernaud-Espinosa, Natalia Rodriguez-Alvarez, James Reynolds, Cristina R Reschke, Ronan M Conroy, Ross C McKiernan, Javier deFelipe, David C Henshall. Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus. Brain structure & function. 2015 Jul;220(4):2387-99