MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset.
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.
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.
Christina
C
Gross
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xiaodi
X
Yao
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Tobias
T
Engel
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Durgesh
D
Tiwari
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Lei
L
Xing
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Shane
S
Rowley
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Scott W
SW
Danielson
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Kristen T
KT
Thomas
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Eva M
EM
Jimenez-Mateos
Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Lindsay M
LM
Schroeder
Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Raymund Y K
RYK
Pun
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.
Steve C
SC
Danzer
Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
David C
DC
Henshall
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.
Gary J
GJ
Bassell
D000818:Animals; D000070416:Antagomirs / Q000235:genetics / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D034743:RNA-Induced Silencing Complex / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051672:Shal Potassium Channels / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013226:Status Epilepticus / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control
D000070416:Antagomirs; D018690:Excitatory Amino Acid Agonists; D035683:MicroRNAs; D034743:RNA-Induced Silencing Complex; D051672:Shal Potassium Channels; D007608:Kainic Acid
Kv4.2; excitotoxicity; miR-324-5p; microRNA; seizure
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