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

Neurobiology of Disease

Christina Gross¹  Darrin H. Brager²  Steve C. Danzer³  Joseph C. Krzeski⁴  Alexander T. Bunk⁴  Nada A. Elsayed⁴  Angela R. White⁴  Lindsay M. Schroeder Carter⁴  Durgesh Tiwari⁴  Jeffrey K. Rymer⁴  Andrew Snider⁴ 

[1] Department of Anesthesia, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA;Center for Learning and Memory, Department of Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA;Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA;Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA;

关键词: microRNA;    Kv4.2;    miR-324-5p;    Epilepsy;    A-type potassium currents;    Antagomir;   

DOI  :  

来源: DOAJ

【 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 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.

【 授权许可】

Unknown