Decreased IH in hippocampal area CA1 pyramidal neurons after perinatal seizure-inducing hypoxia

Abstract

Purpose: The hyperpolarization-activated cation current (IH) has been proposed to play a role in some forms of epileptogenesis, as it critically regulates synaptic integration and intrinsic excitability of principal limbic neurons and can be pathologically altered after experimentally induced seizures. In hippocampal CA1 pyramidal neurons, IH is functionally decreased after kainate-induced status epilepticus in adult rats but is increased after hyperthermia-induced seizures in immature rat pups. This study aimed to determine whether and how IH may be altered in CA1 pyramidal neurons after seizure-inducing global hypoxia in the neonatal brain.

Methods: Seizures were induced in rat pups on postnatal day 10 by 14- to 16-min exposure to 5-7% O2. Whole-cell patch-clamp recordings were obtained from hippocampal CA1 pyramidal neurons in slices 30 min to 3 days after hypoxia treatment, and from control age-matched littermates. IH was isolated under voltage-clamp by subtracting current responses to hyperpolarizing voltage steps before and during application of the IH blocker ZD 7288 (100 microM).

Results: IH was significantly decreased in pyramidal neurons from the hypoxia-treated group compared with controls (p<0.001; 19 controls; 15 hypoxia). Analyses of tail currents and activation kinetics indicated no statistically significant differences between groups in the voltage dependence or time constants of activation.

Conclusions: These data indicate that a single episode of neonatal hypoxia that induces seizures can persistently decrease IH in CA1 pyramidal neurons, raising this as a potential contributing mechanism to epileptogenesis in this setting. Our findings further indicate that the consequences of seizures for IH may depend more on seizure etiology than on maturational stage.