Epileptiform activity induced by lowering extracellular [Mg 2+] in combined hippocampal-entorhinal cortex slices: Modulation by receptors for norepinephrine and N-methyl- d-aspartate

Abstract

Reduction of extracellular Mg 2+ concentration induced spontaneous and evoked epileptiform activity in the entorhinal cortex (EC) and dentate gyrus (DG) of combined hippocampus (HC)-EC slices. Extracellular field potentials, as well as changes in extracellular Ca 2+ and K + concentrations, were measured in EC and DG with ion-selective/reference electrodes during both repetitive and single stimuli. In the EC, lowering extracellular [Mg 2+] induces both spontaneous and single stimulus evoked ictal events consisting of extracellular negative potential shifts (up to 5 mV, 30 sec), decreases in [Ca 2+] 0 and increases in [K +] 0. In the DG, spontaneous events were much shorter, but similar changes in [Ca 2+] 0, [K +] 0 and field potentials (FPs) could be evoked by brief high-frequency stimulation. In both areas, the N-methyl- d-aspartate (NMDA) receptor antagonist 2-aminophosphonovalerate (2-APV) completely blocked spontaneous as well as stimulus evoked epileptiform events. The neurotransmitter norepinephrine (NE), which has previously been shown to modulate long-term potentiation in the DG, was found to exhibit differential modulation of epileptiform activity in the EC and DG. In the EC, NE, acting via α 1-receptors, completely blocked low Mg 2+-induced epileptiform activity. In contrast, in the DG, NE exhibited a β-receptor mediated prolongation of the low Mg 2+-induced ictal events, and enhanced the stimulus-induced ionic and field potential changes. From these results, we conclude that lowering extracellular [Mg 2+], acting in large part through the removal of the Mg 2+ voltage-dependent blockade of NMDA receptors, leads to induction of epileptiform activity in both the EC and DG. However, spontaneous ictal events were most prominent in the EC, suggesting an importance of this area in seizure generation. Furthermore, NE exhibits a complementary modulatory action in the EC and DG, one which would enhance signal transmission through the DG and simultaneously reduce input noise from the EC, as well as exerting a potent antiepileptogenic action in this area.