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

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

Author information

1
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
2
Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA.
3
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Anesthesia, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
4
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: christina.gross@cchmc.org.

Abstract

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

PMID:
31212067
PMCID:
PMC6689429
[Available on 2020-10-01]
DOI:
10.1016/j.nbd.2019.104508

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