MicroRNA-Mediated Regulation of Kv4.2 and Its Effects on EEG Power, Seizure Susceptibility, and Interictal Spike Activity in Mouse Models of Epilepsy

Abstract

By Alex Bunk, Chemistry

Advisor: Durgesh Tiwari

Presentation ID: PM_D13

Abstract: Epilepsy is a neurological disorder characterized by recurrent seizures affecting and is uncontrolled in one third of patients. To develop novel, more effective treatments, it is important to understand the underlying mechanisms. This study used electroencephalography (EEG) in different mouse models of epilepsy to reveal how regulation of potassium channel Kv4.2 by microRNAs (miRNAs) affects seizure frequency and interictal epileptiform activity. Kv4.2 is an important regulator of neuronal excitability, and its expression is reduced after chemically induced seizures and in mouse models of epilepsy. A recent study from our lab has demonstrated that an antagonist of miR-324-5p (antagomir) increases Kv4.2 expression in mouse models of epilepsy and prolongs the latency to onset of a chemically induced seizure. The work presented here investigates the effects of miRNA antagomir treatment on EEG power, interictal spike activity, seizure susceptibility, and neuronal degeneration in genetic (CNTNAP2) and induced (pilocarpine) mouse models of epilepsy. MiR-324-5p antagomir treatment reduced seizure occurrence in the pilocarpine model but had no effect in the CNTNAP2 mice. No significant effect of antagomir treatment on EEG power in either model was observed. A reduction of interictal spike activity in the pilocarpine model, but not in the CNTNAP2 mice was observed. Additional investigation using a mouse model with reduced Kv4.2 expression showed increased EEG power and interictal spike activity in Kv4.2 knockout and heterozygous mice compared to wild type. These findings suggest that Kv4.2 expression and miR-324-5p are important factors in the regulation of neuronal excitability in epilepsy.