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 byspontaneous episodes of abnormal synchronized neuronal activity.Calcium-permeable AMPA receptors (CP-AMPARs) are hypothesized tobe a promising target for pharmacological intervention in epilepsybecause they play a significant role in the potentiation of glutamatergicsynapses. In this study, we investigated the effects of CP-AMPAR blockadeon the development of epileptiform activity in mouse entorhinalcortex slices using the selective blocker IEM-1460. Epileptiformactivity was induced by 4-aminopyridine-containing perfusing solution withincreased potassium ion concentration and decreased magnesium ionconcentration. To register the membrane potential of neurons ofdeep layers of the entorhinal cortex, the whole-cell patch-clamp methodwas used. The activity of both pyramidal neurons and inhibitoryinterneurons was recorded. The simultaneous registration of twocells of the aforementioned types demonstrated that interneuronactivity is predominant prior to an ictal discharge. Pharmacologicalblockade of CP-AMPARs resulted in an increase in the frequency ofGABAergic preictal discharges and an increase in the duration ofictal activity. Thus, blockade of CP-AMPARs has a pronounced proepilepticeffect that is not associated with a decrease in the activity ofinhibitory interneurons. These results suggest that the proepilepticeffect of CP-AMPARs blockade may be due to an increase in the probabilityof generation of short bursts of activity preceding and constitutingthe ictal discharge.