Characterizing concentration-dependent neural dynamics of 4-aminopyridine-induced epileptiform activity

Abstract

Epilepsy remains one of the most common neurological disorders. In patients, it is characterized by unprovoked, spontaneous, and recurring seizures or ictal events. Typically, inter-ictal events or large bouts of population level activity can be measured between seizures and are generally asymptomatic. Decades of research has focused on understanding the mechanisms leading to the development of seizure-like activity using various proconvulsive pharmacological agents, including 4-aimnopyridine (4AP). However, the lack of consistency in the concentrations used for studying 4AP-induced epileptiform activity in animal models may give rise to differences in the results and interpretation thereof. Indeed, the range of 4AP concentration in both in vivo and in vitro studies varies from 3µM to 40mM. Here, we explored the effects of various 4AP concentrations on the development and characteristics of hippocampal epileptiform activity in acute mouse brain slices of either sex. Using multielectrode array recordings, we show that 4AP induces hippocampal epileptiform activity for broad range of concentrations. The frequency component and the spatio-temporal patterns of the epileptiform activity revealed a dose-dependent response. Finally, in the presence of 4AP, reduction of KCC2 co-transporter activity by KCC2 antagonist VU0240551 prevented the manifestation of the frequency component differences between different concentrations of 4AP. Overall, the study predicts that different concentrations of 4AP can result in the different mechanisms behind hippocampal epileptiform activity, of which some are dependent on the KCC2 co-transporter function.