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Cell Rep. 2016 Sep 27;17(1):37-45. doi: 10.1016/j.celrep.2016.08.074.

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

Author information

1
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: christina.gross@cchmc.org.
2
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
4
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
5
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
6
Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA; Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Anesthesiology, University of Cincinnati, Cincinnati, OH 45229, USA.
7
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.

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.

KEYWORDS:

Kv4.2; excitotoxicity; miR-324-5p; microRNA; seizure

PMID:
27681419
PMCID:
PMC5061042
DOI:
10.1016/j.celrep.2016.08.074
[Indexed for MEDLINE]
Free PMC Article

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