Abstract
Somatic recordings from CA1 pyramidal cells indicated a persistent upregulation of the h-current (Ih) after experimental febrile seizures. Here, we examined febrile seizure-induced long-term changes in Ih and neuronal excitability in CA1 dendrites. Cell-attached recordings showed that dendritic Ih was significantly upregulated, with a depolarized half-activation potential and increased maximal current. Although enhanced Ih is typically thought to be associated with decreased dendritic excitability, whole-cell dendritic recordings revealed a robust increase in action potential firing after febrile seizures. We turned to computational simulations to understand how the experimentally observed changes in Ih influence dendritic excitability. Unexpectedly, the simulations, performed in three previously published CA1 pyramidal cell models, showed that the experimentally observed increases in Ih resulted in a general enhancement of dendritic excitability, primarily due to the increased Ih-induced depolarization of the resting membrane potential overcoming the excitability-depressing effects of decreased dendritic input resistance. Taken together, these experimental and modeling results reveal that, contrary to the exclusively anti-convulsive role often attributed to increased Ih in epilepsy, the enhanced Ih can co-exist with, and possibly even contribute to, persistent dendritic hyperexcitability following febrile seizures in the developing hippocampus.
Highlights
Fever-induced seizures are the most common form of childhood seizures, occurring in 3–5% of infants (Shinnar and Glauser, 2002)
We report that (1) Three to 4 weeks after experimental febrile seizures, cell-attached dendritic recordings showed that Ih was persistently upregulated in CA1 pyramidal cell dendrites, characterized by depolarized half-activation potential and altered kinetics; (2) In whole cell recordings, dendrites from animals that experienced experimental febrile seizures showed markedly enhanced excitability when tested from the resting membrane potential (RMP)
This increased excitability was not eliminated after compensation of the depolarized post-febrile dendritic RMP, indicating that unidentified currents other than Ih may play a role in long-term, dendritic hyperexcitability after febrile seizures; (3) Simulations implementing the experimentally determined h-current alterations in published CA1 neuron models predicted that the observed Ih changes may contribute to hyperexcitability
Summary
Fever-induced (febrile) seizures are the most common form of childhood seizures, occurring in 3–5% of infants (Shinnar and Glauser, 2002). Because of the potential clinical association of prolonged (>15 min) febrile seizures with persistent temporal lobe epilepsy, it is important to understand how prolonged seizures in the developing brain alter neuronal excitability (Annegers et al, 1987; Baram et al, 1997; Chen et al, 2007; Schuchmann et al, 2006). In the rat hyperthermia model of experimental febrile seizures (HT) (Baram et al, 1997; Dube et al, 2000, 2006), whole cell somatic patch clamp recordings from CA1 pyramidal neurons demonstrated long-term upregulation of Ih with a depolarized half-activation potential and slower kinetics (Chen et al, 2001).
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