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

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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.

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Acknowledgments

The authors would like to thank Julika Pitsch and Albert Becker for advice on the pilocarpine model and Emilie Petit and John L. Waddington for advice on behavior testing. This work was supported by funding awards from Science Foundation Ireland (11/TIDA/B1988), Health Research Board (HRA-POR-2013-325), US National Institute of Neurological Disorders and Stroke award R56 073714 and the Spanish Ministerio de Economía y Competitividad grants BFU2012-34963 and CIBERNED (CB06/05/0066) (JD).

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Authors and Affiliations

  1. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland

    Eva M. Jimenez-Mateos, Tobias Engel, Natalia Rodriguez-Alvarez, James Reynolds, Cristina R. Reschke, Ross C. McKiernan & David C. Henshall

  2. Laboratorio Cajal de Circuitos Corticales (CTB), Instituto Cajal (CSIC) and CIBERNED, Universidad Politécnica de Madrid, Madrid, Spain

    Paula Merino-Serrais, Isabel Fernaud-Espinosa & Javier deFelipe

  3. Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland

    Ronan M. Conroy

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  1. Eva M. Jimenez-Mateos
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  2. Tobias Engel
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  3. Paula Merino-Serrais
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  4. Isabel Fernaud-Espinosa
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  7. Cristina R. Reschke
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  10. Javier deFelipe
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  11. David C. Henshall
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Correspondence to David C. Henshall.

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Jimenez-Mateos, E.M., Engel, T., Merino-Serrais, P. et al. Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus. Brain Struct Funct 220, 2387–2399 (2015). https://doi.org/10.1007/s00429-014-0798-5

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