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

NEUROBIOLOGY OF DISEASE

卷:130

Article

Tiwari, Durgesh¹  Brager, Darrin H.²  Rymer, Jeffrey K.¹  Bunk, Alexander T.¹  White, Angela R.¹  Elsayed, Nada A.¹  Krzeski, Joseph C.¹  Snider, Andrew¹  Carter, Lindsay M. Schroeder¹  Danzer, Steve C.^3,4,5  Gross, Christina^1,5 

[1] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA

[2] Univ Texas Austin, Dept Neurosci, Ctr Learning & Memory, Austin, TX 78712 USA

[3] Cincinnati Childrens Hosp Med Ctr, Dept Anesthesia, Cincinnati, OH 45229 USA

[4] Univ Cincinnati, Coll Med, Dept Anesthesia, Cincinnati, OH 45229 USA

[5] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA

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

DOI  :  10.1016/j.nbd.2019.104508

来源: Elsevier

【 摘 要 】

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 CAl 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 CAl 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.

【 授权许可】

Free