The role of the hyperpolarization-activated cationic current Ih in the timing of interictal bursts in the neonatal hippocampus

Abstract

Under both pathological and experimental conditions, area CA3 of the adult or juvenile hippocampus generates periodic population discharges known as interictal bursts. Whereas the ionic and synaptic basis of individual bursts has been comprehensively studied experimentally and computationally, the pacemaker mechanisms underlying interictal rhythmicity remain conjectural, We showed previously that rhythmic population discharges resembling interictal bursts can be induced in hippocampal slices from first postnatal week mice, in Mg2+-free solution with GABAA receptor-mediated inhibition blocked. Here we show that these neonatal bursts occurred with high temporal precision and that their frequency and regularity were greatly reduced by the bradycardic agent ZD-7288 when applied at concentrations and durations that selectively block the hyperpolarization-activated, cationic current Ih. Augmenting Ih by elevating intracellular cAMP dramatically increased burst frequency in a protein kinase A-independent manner. Burst amplitudes were strongly correlated with the preceding, but not the following, interburst intervals. The experimentally observed distribution of interburst intervals was modeled by assuming that a burst was triggered whenever the instantaneous rate of spontaneous EPSPs (sEPSPs) exceeded a threshold and that the mean sEPSP rate was minimal immediately after a burst and then relaxed exponentially to a steady-state level. The effect of blocking Ih in any given slice could be modeled by decreasing only the steady-state sEPSP rate, suggesting that the instantaneous rate of sEPSPs is governed by the level of Ih activation and raising the novel possibility that interburst intervals reflected the slow activation kinetics of Ih in the neonatal CA3.