Epileptiform hyperexcitability in the rat neocortex: modulation by the H current blocker ZD7288

Objectives: Neurons in the CNS respond to intracellular injection of hyperpolarizing current pulses by generating depolarizing sags contributed by a cation current termed Ih. Ih modulates neuron excitability and rhythmicity. However, whether the net effect of Ih on cortical networks results in facilitation or depression of epileptiform activity remains debatable. Here, we addressed this issue by studying the effects of the Ih blocker ZD7288 on the epileptiform discharges.Methods: We studied with field and intracellular recordings the effects of the Ih blocker ZD7288 on the epileptiform discharges (duration=2.54±0.33s, mean±SEM; interval of occurrence=34.2±3.3s, n=30) induced in rat neocortical slices by bath applying 4- aminopyridine+picrotoxin+CGP55845.Results: ZD7288 (10–100µM; n=18) abolished the depolarizing sags seen during injection of intracellular hyperpolarizing current pulses while increasing both resting membrane potential and apparent input resistance. These effects were fully established with 10µM ZD7288 and were accompanied by a dosedependent decrease in the occurrence of spontaneous epileptiform events and a reduction in their duration (this last effect becoming apparent with concentrations >20µM). ZD7288 (10–100µM; n=17) also caused a dose-dependent decrease of background postsynaptic potentials. Finally, 10, 50 or 100µM ZD7288 (n=6, 5 and 8, respectively) depressed the epileptiform activity during application of Cs+, which is known to reduce Ih.Conclusion: This evidence indicates that ZD7288 depresses neocortical epileptiform synchronization. However, most of this action may reflect the ability of ZD7288 to interfer with synaptic transmission.