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Author Notes:

Email: christina.gross@cchmc.org

C.G., X.Y. and G.J.B. perceived of the study.

C.G., X.Y., L.X., R.Y.K.P, S.C.D, D.C.H. and G.J.B. designed and analyzed experiments, C.G., X.Y., T.E., D.T., L.X., S.W.D., K.T.T., L.M.S. and E.M.J. performed and analyzed experiments, S.R. analyzed experiments.

C.G. coordinated and supervised the study and wrote the manuscript.

All authors read and revised the manuscript.

The authors thank Dr. Jeanne Nerbonne for providing the Kcnd2 KO mice, and Ashwini Poopal, Nina Patel, Qiaoyun Gong, and Nada El-Sayed for technical assistance.

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Research Funding:

This research was supported by a Research Grant by the Epilepsy Foundation (C.G.), an Emory University Research Council grant (C.G.), a Trustee Award by the Cincinnati Children’s Research Foundation (C.G.), NIH Grants 1R01NS092705 (C.G.), 1R21NS089080 (G.J.B.), 1R21DA033478 (G.J.B.), Cell Reports 17, 37–45, September 27, 2016 43 and 2R01NS062806 (S.C.D.), Science Foundation Ireland grants 13/SIRG/ 2014 (E.M.J.), 13/SIRG/2098, 12/COEN/18 (T.E.), and 13/IA/1891 (D.C.H.), Health Research Board (HRA-POR-2013-325) (D.C.H.) and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602130 (D.C.H.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • MENTAL-RETARDATION PROTEIN
  • MESSENGER-RNA TRANSLATION
  • TEMPORAL-LOBE EPILEPSY
  • CA1 PYRAMIDAL NEURONS
  • HIPPOCAMPAL-NEURONS
  • K+ CURRENT
  • EXPRESSION
  • BRAIN
  • GENE
  • EXCITABILITY

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

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Journal Title:

Cell Reports

Volume:

Volume 17, Number 1

Publisher:

, Pages 37-45

Type of Work:

Article | Final Publisher PDF

Abstract:

Seizures are bursts of excessive synchronized neuronal activity, suggesting that mechanisms controlling brain excitability are compromised. The voltage-gated potassium channel Kv4.2, a major mediator of hyperpolarizing A-type currents in the brain, is a crucial regulator of neuronal excitability. Kv4.2 expression levels are reduced following seizures and in epilepsy, but the underlying mechanisms remain unclear. Here, we report that Kv4.2 mRNA is recruited to the RNA-induced silencing complex shortly after status epilepticus in mice and after kainic acid treatment of hippocampal neurons, coincident with reduction of Kv4.2 protein. We show that the microRNA miR-324-5p inhibits Kv4.2 protein expression and that antagonizing miR-324-5p is neuroprotective and seizure suppressive. MiR-324-5p inhibition also blocks kainic-acid-induced reduction of Kv4.2 protein in vitro and in vivo and delays kainic-acid-induced seizure onset in wild-type but not in Kcnd2 knockout mice. These results reveal an important role for miR-324-5p-mediated silencing of Kv4.2 in seizure onset.

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© 2016 The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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