MicroRNA inhibition upregulates hippocampal A-type potassium current and reduces seizure frequency in a mouse model of epilepsy

Neurobiol Dis. 2019 Oct:130:104508. doi: 10.1016/j.nbd.2019.104508. Epub 2019 Jun 15.


Epilepsy is often associated with altered expression or function of ion channels. One example of such a channelopathy is the reduction of A-type potassium currents in the hippocampal CA1 region. The underlying mechanisms of reduced A-type channel function in epilepsy are unclear. Here, we show that inhibiting a single microRNA, miR-324-5p, which targets the pore-forming A-type potassium channel subunit Kv4.2, selectively increased A-type potassium currents in hippocampal CA1 pyramidal neurons in mice. Resting membrane potential, input resistance and other potassium currents were not altered. In a mouse model of acquired chronic epilepsy, inhibition of miR-324-5p reduced the frequency of spontaneous seizures and interictal epileptiform spikes supporting the physiological relevance of miR-324-5p-mediated control of A-type currents in regulating neuronal excitability. Mechanistic analyses demonstrated that microRNA-induced silencing of Kv4.2 mRNA is increased in epileptic mice leading to reduced Kv4.2 protein levels, which is mitigated by miR-324-5p inhibition. By contrast, other targets of miR-324-5p were unchanged. These results suggest a selective miR-324-5p-dependent mechanism in epilepsy regulating potassium channel function, hyperexcitability and seizures.

Keywords: A-type potassium currents; Antagomir; Epilepsy; Epileptiform spikes; Kv4.2; RISC; RNA-induced silencing complex; Seizures; miR-324-5p; microRNA.

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epilepsy / metabolism
  • Epilepsy / physiopathology*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Seizures / metabolism
  • Seizures / physiopathology*
  • Shal Potassium Channels / genetics
  • Shal Potassium Channels / metabolism*
  • Up-Regulation*


  • MicroRNAs
  • Shal Potassium Channels