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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antagomirs / genetics
  • Antagomirs / metabolism
  • Excitatory Amino Acid Agonists / pharmacology*
  • Gene Expression Regulation
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Kainic Acid / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Primary Cell Culture
  • RNA-Induced Silencing Complex / genetics
  • RNA-Induced Silencing Complex / metabolism
  • Seizures / chemically induced
  • Seizures / genetics*
  • Seizures / pathology
  • Seizures / prevention & control
  • Shal Potassium Channels / genetics*
  • Shal Potassium Channels / metabolism
  • Signal Transduction
  • Status Epilepticus / chemically induced
  • Status Epilepticus / genetics*
  • Status Epilepticus / pathology
  • Status Epilepticus / prevention & control


  • Antagomirs
  • Excitatory Amino Acid Agonists
  • MicroRNAs
  • RNA-Induced Silencing Complex
  • Shal Potassium Channels
  • Kainic Acid