Abstracts

Rationale: Changes in the hyperpolarization activated, mixed cation current Ih has been implicated in several seizure models, commonly linking a downregulation of Ih to increased neuronal input resistance causing increased responses to excitatory input (Shah et al., 2004;Strauss et al., 2004;Zhang et al., 2006). However, in the hyperthermia (HT) experimental model of prolonged febrile seizures, somatic recordings showed an upregulation of Ih with altered kinetics interacting with increased perisomatic inhibition in CA1 pyramidal neurons contributing to increased excitability (Chen et al., 2001). We performed dendritic patch-clamp experiments combined with compartmental modeling to investigate whether a potentially upregulated dendritic Ih contributes to hyper-excitability following experimental febrile seizures.Methods: Following induction of prolonged experimental febrile seizures at P10-P11, cell-attached and whole-cell patch clamp recordings were made from CA1 pyramidal cell apical dendrites in acute slices from 4-5 week old control and experimental (HT) Sprague-Dawley rats. The underlying mechanisms of the hyper-excitability were further examined in a multi-compartmental single cell model in NEURON.Results: Cell-attached recordings of Ih in CA1 pyramidal cell apical dendrites 200 μm from the soma showed a 68% increase in current density along with a 6.7 mV depolarized shift in half-activation voltage as well as slower activation and de-activation kinetics in slices from HT animals. Whole cell dendritic recordings revealed a 3.7 mV depolarized resting membrane potential in HT dendrites and an 89% increase in the number of back-propagated action potentials in response to depolarizing current injections compared to controls. The increase in action-potential firing was abolished by wash-in of the h-current blocker ZD 7288. Using a previously published multi-compartmental model of CA1 pyramidal cell, the effects of the altered Ih characteristics were further investigated.Conclusions: Using direct patch-clamp measurements, we have demonstrated that experimental febrile seizures lead to an upregulation of Ih current density with depolarized half-activation voltage and slower kinetics in hyperexcitable CA1 pyramidal cell dendrites.

Acknowledgment: This study was supported by the Epilepsy Foundation/Milken Family Foundation (EFA-36656 to JDJ) and the NIH (NS38580 to IS).