Abstract
Epilepsy remains one of the most common neurological disorders. In patients, it is characterized by unprovoked, spontaneous, and recurrent 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 have focused on understanding the mechanisms leading to the development of seizure-like activity using various pro-convulsive 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 results and interpretation thereof. Indeed, the range of 4AP concentration in both in vivo and in vitro studies varies from 3 μM to 40 mM. 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 multi-electrode array recordings, we show that 4AP induces hippocampal epileptiform activity for a broad range of concentrations.The frequency component and the spatiotemporal 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.
Highlights
Potassium (K+) channel activation has been shown to be responsible for the repolarization of the membrane potential following the depolarization phase of an action potential [1,2,3,4,5]
Bath applied 4AP at all concentrations tested in this study (25 μM-200 μM) resulted in a transition from quiescence to a seizure-like state characterized by stereotyped continuous epileptiform activity (Figure 1)
Single channel recordings from CA1, CA3, and dentate gyrus (DG) revealed a bias towards CA3 as the generator of the largest epileptiform activity (Figures 1C and 1E)
Summary
Potassium (K+) channel activation has been shown to be responsible for the repolarization of the membrane potential following the depolarization phase of an action potential [1,2,3,4,5]. Outward going K+ A-type currents (IA) have been shown to regulate the action potential firing rate by modulating the inter-spike interval in response to sub-threshold current injections [2,3,4,5]. Experiments in rat hippocampal neurons have shown that most of the K+ current underlying the repolarization phase of an action potential can be accounted for by the IA and the dendrotoxin-sensitive K+ D-current (ID) [3]. Due to its important role in regulating neuronal excitability, it is not surprising that the IA has been the subject of intense study in its relation to epileptic seizures
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