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

• Type of Material: Article
• Authors: Christina Gross, Cincinnati Children’s Hospital Medical; Xiaodi Yao, Emory University; Tobias Engel, Royal College of Surgeons in Ireland; Durgesh Tiwari, Cincinnati Children’s Hospital Medical Center; Li Xing, Emory University; Shane Rowley, Cincinnati Children’s Hospital Medical Center; Scott Walter Danielson, Emory University; Kristen Therese Thomas, Emory University; Eva Maria Jimenez-Mateos, Royal College of Surgeons in Ireland; Lindsay Michelle Schroeder, Cincinnati Children’s Hospital Medical Center; Raymund Yu Kwan Pun, Cincinnati Children’s Hospital Medical Center; Steve CraigDanzer Danzer, University of Cincinnati; David Clifford Henshall, Royal College of Surgeons in Ireland; Gary Bassell, Emory University
• Language: English
• Date: 2016-09-27
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2016.08.074
• Title of Journal or Parent Work: Cell Reports
• Volume: 17
• Issue: 1
• Start Page: 37
• End Page: 45
• Grant/Funding Information: 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: CA1 PYRAMIDAL NEURONS; TEMPORAL-LOBE EPILEPSY; Science & Technology; Cell Biology; Life Sciences & Biomedicine; K+ CURRENT; EXPRESSION; HIPPOCAMPAL-NEURONS; MENTAL-RETARDATION PROTEIN; EXCITABILITY; GENE; MESSENGER-RNA TRANSLATION; BRAIN
• Research Categories: Biology, Physiology; Biology, Cell; Biology, Neuroscience

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.