The H current blocker ZD7288 decreases epileptiform hyperexcitability in the rat neocortex by depressing synaptic transmission

Abstract

Neurons respond to intracellular injection of hyperpolarizing current pulses by generating depolarizing sags contributed by a cation current termed I h. I h modulates neuron excitability and rhythmicity. It is, however, unclear whether the net effect of changing I h leads to facilitation or depression of cortical epileptiform activity. Here, we addressed this issue by using field and intracellular recordings to study the effects of ZD7288 (10–100 μM), a bradycardic agent known to abolish I h, on the epileptiform discharges (duration = 2.5 ± 0.3 s, mean ± SEM; interval of occurrence = 34.2 ± 3.3 s, n = 30 slices) induced in rat neocortical slices by 4-aminopyridine and GABA receptor antagonists. ZD7288 abolished the depolarizing sags seen during injection of intracellular hyperpolarizing current pulses while increasing resting membrane potential and apparent input resistance. These effects, which were fully established with 10 μM ZD7288, were associated with a dose-dependent decrease in the occurrence of spontaneous epileptiform events and a reduction in their duration (the latter change occurring at doses >20 μM). ZD7288 also caused a dose-dependent decrease of background postsynaptic potentials. Finally, ZD7288 could depress epileptiform activity during Cs + pre-treatment, a procedure known to block I h. These data indicate that ZD7288 hampers neocortical epileptiform synchronization, but also suggest that most of this action reflects the ability of ZD7288 to decrease synaptic transmission.