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. Kv...
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Veröffentlicht in: | Cell reports (Cambridge) 2016-09, Vol.17 (1), p.37-45 |
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Zusammenfassung: | 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.
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•Kv4.2 mRNA is recruited to the miRNA-induced silencing complex after seizure•Kv4.2 mRNA is a specific target of the microRNA miR-324-5p•Antagonizing miR-324-5p counteracts seizure-induced reduction of Kv4.2 protein•Antagonizing miR-324-5p delays seizure onset in wild-type but not in Kcnd2 KO mice
Gross et al. show that the voltage-gated potassium channel Kv4.2 is regulated by microRNA-induced silencing during seizures. Inhibition of the Kv4.2-targeting microRNA miR-324-5p increases Kv4.2 protein levels, counteracts seizure-induced Kv4.2 downregulation, suppresses kainic-acid-evoked seizures and cell death, and delays seizure onset in wild-type, but not in Kcnd2 knockout mice. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2016.08.074 |