Summary:Purpose: The hyperpolarization-activated cation current (I H ) 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, I H 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 I H 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% O 2 . Whole-cell patchclamp recordings were obtained from hippocampal CA1 pyramidal neurons in slices 30 min to 3 days after hypoxia treatment, and from control age-matched littermates. I H was isolated under voltage-clamp by subtracting current responses to hyperpolarizing voltage steps before and during application of the I H blocker ZD 7288 (100 μM).Results: I H 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 I H 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 I H may depend more on seizure etiology than on maturational stage.

The hyperpolarization-activated cation current IH regulates the electrical activity of many excitable cells, but its precise function varies across cell types. The antiepileptic drug lamotrigine (LTG) recently was shown to enhance IH in hippocampal CA1 pyramidal neurons, revealing a potential anticonvulsant mechanism, as IH can dampen dendrito-somatic propagation of excitatory postsynaptic potentials in these cells. However, IH also is expressed in many hippocampal interneurons that provide synaptic inhibition to CA1 pyramidal neurons, and thus, IH modulation may indirectly regulate inhibitory control of principal cells via direct modulation of interneuron activity. Whether IH in hippocampal interneurons is sensitive to modulation by LTG, and how this may affect synaptic inhibition of pyramidal cells has not been investigated. In this study, we examined the effects of LTG on IH and spontaneous firing of area CA1 s.o. interneurons, and on spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in immature rat brain slices. LTG (100 µM) significantly increased IH in the majority of interneurons, and depolarized interneurons from rest, promoting spontaneous firing. LTG also caused an increase in the frequency of spontaneous (but not miniature) IPSCs in pyramidal neurons without significantly altering amplitudes or rise and decay times. These data indicate that IH in CA1 interneurons can be increased by LTG, similarly to IH in pyramidal neurons, that IH enhancement increases interneuron excitability, and that these effects are associated with increased basal synaptic inhibition of CA1 pyramidal neurons.

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