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Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects

Abstract

Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation.

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Figure 1: MiR-134 upregulation after status epilepticus and in epilepsy.
Figure 2: Antagomir-mediated silencing of miR-134 in mouse hippocampus.
Figure 3: Antagomir silencing of miR-134 reduces hippocampal CA3 spine density in vivo.
Figure 4: Antagomir silencing of miR-134 reduces seizure severity during status epilepticus.
Figure 5: Antagomir silencing of miR-134 protects against status epilepticus in vivo and kainic acid toxicity in vitro.
Figure 6: Antagomir silencing of miR-134 after status epilepticus reduces the number of epileptic seizures and protects against progressive TLE pathology.

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Acknowledgements

We would like to thank J. Varley, J. Phillips and members of the Epilepsy Programme, Beaumont Hospital. We thank S. Miller-Delaney for assistance and N. Plesnila, J. Prehn and R. Simon for helpful suggestions on the manuscript. We thank the Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, Maryland. This work was supported by funding from Science Foundation Ireland awards 08/IN1/B1875 (D.C.H., E.M.J.-M., K.T., G.M. and T.S.), 11/TIDA/B1988 (D.C.H.) and 07/IN.1/B960 (J.W. and C.O.), US National Institute of Neurological Disorders and Stroke award R56 073714 (D.C.H.), an Irish Research Council for Science, Engineering and Technology postdoctoral fellowship (E.M.J.-M.), Irish Health Research Board grant PHD/2007/11 (R.C.M.) and the Spanish Ministry of Education, Science and Innovation grant SAF2009-09394 (J.D.).

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E.M.J.-M. performed expression analyses, tissue culture, spine imaging, histology and epilepsy monitoring. T.E., K.T., G.M. and T.S. performed mouse modeling and telemetry. P.M.-S. and J.D. performed spine injections and data analysis. R.C.M. and S.P. performed expression studies. C.O. and J.L.W. conducted and analyzed the behavioral studies. N.D., D.F.O. and M.A.F. organized the human studies. R.M.C. performed statistical analyses. R.L.S. contributed to study design and analysis. D.C.H. and E.M.J.-M. conceived of the study, analyzed data and wrote the manuscript.

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Correspondence to David C Henshall.

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The authors declare no competing financial interests.

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Jimenez-Mateos, E., Engel, T., Merino-Serrais, P. et al. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med 18, 1087–1094 (2012). https://doi.org/10.1038/nm.2834

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