The Calcium-Permeable AMPA Receptor Blocker IEM-1460 Increases the Intensity of Epileptiform Activity in the Entorhinal Cortex of Mice in vitro

Epilepsy is a common neurological disorder characterized by spontaneous episodes of abnormal synchronized neuronal activity. Calcium-permeable AMPA receptors (CP-AMPARs) are hypothesized to be a promising target for pharmacological intervention in epilepsy because they play a significant role in the potentiation of glutamatergic synapses. In this study, we investigated the effects of CP-AMPAR blockade on the development of epileptiform activity in mouse entorhinal cortex slices using the selective blocker IEM-1460. Epileptiform activity was induced by 4-aminopyridine-containing perfusing solution with increased potassium ion concentration and decreased magnesium ion concentration. To register the membrane potential of neurons of deep layers of the entorhinal cortex, the whole-cell patch-clamp method was used. The activity of both pyramidal neurons and inhibitory interneurons was recorded. The simultaneous registration of two cells of the aforementioned types demonstrated that interneuron activity is predominant prior to an ictal discharge. Pharmacological blockade of CP-AMPARs resulted in an increase in the frequency of GABAergic preictal discharges and an increase in the duration of ictal activity. Thus, blockade of CP-AMPARs has a pronounced proepileptic effect that is not associated with a decrease in the activity of inhibitory interneurons. These results suggest that the proepileptic effect of CP-AMPARs blockade may be due to an increase in the probability of generation of short bursts of activity preceding and constituting the ictal discharge.