Summary:Purpose: The h current (Ih) is an inwardly mixed cationic conductance activated by membrane hyperpolarization and distributed predominantly in the apical dendrites of hippocampal pyramidal neurons. To verify a hypothesis that an anomalous hyperpolarization generates an abnormal excitation by way of Ih channels, we examined the effects of Ih blockers (CsCl and ZD7288) on electrically induced paroxysmal discharges (PADs).Methods: Fifty-three adult male rabbits were used. We measured the PAD threshold elicited by stimulation to the apical dendritic layer of the hippocampal CA1 region before and after injecting 50 l of each Ih blocker or saline extracellularly into the same region.Results: In Ih blocker injection groups (n ‫ס‬ 26), we obtained a significant increase in PAD threshold (1 mM CsCl: 163%, p < 0.01; 10 mM CsCl: 265%, p < 0.01; 100 mM CsCl: 199%, p < 0.01; 100 M ZD7288: 192%, p < 0.05; 1 mM ZD7288: 246%, p < 0.05). Conversely, we did not obtain the increase in PAD threshold in a saline injection group (n ‫ס‬ 10, 107%). The magnitude as well as duration of the effect had a tendency to depend on concentration of Ih blockers, although a saturated or declining tendency was observed with the 100 mM CsCl injection.Conclusions: We concluded that Ih channels might contribute to hippocampal epileptiform discharges in vivo. Our hypothesis for epileptogenesis demonstrated in the present experiment offers an idea to develop a new type of antiepileptic drug based on Ih blockers for the treatment of epileptic disorders refractory to current medications. Key Words: EpilepsyHippocampus-Paroxysmal discharge-Hyperpolarizationactivated current-In vivo physiology.Multiple ionic channels regulate neuronal activity. In the hippocampal CA1 region, Na + and Ca 2+ channels activate and inactivate neuronal membrane depolarizations and contribute to the generation of excitatory postsynaptic potentials (1-3). Before as well as after the membrane excitation, the release of ␥-aminobutyric acid from inhibitory interneurons induces inhibitory postsynaptic potentials (IPSPs) and suppresses/terminates the depolarizing potentials (4-6). Previous hypotheses for epileptogenesis were based on imbalance between such excitatory and inhibitory currents (7).Recently the h current (Ih) has been investigated (8-24), and the following characteristics of Ih were reported: (a) Ih is a voltage-gated nonselective cationic conductance activated by membrane hyperpolarization, not by depolarization (8,14); (b) Ih is blocked by cesium chloride (CsCl) or 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) instead of tetrodotoxin (8,13,15); and (c) Ih channels occur in higher density in the apical dendrites than in the soma (8,14). In spite of many in vitro reports on Ih channels (8-24) as well as in vivo studies on the pacemaking function of Ih (25-28), any contributions of Ih to epileptic activity are unknown in vivo, except for the one that showed the long-lasting enhancement of the widely expressed intrinsic Ih that converts...

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