Upregulated H-Current in hyperexcitable CA1 dendrites after febrile seizures

Abstract

Somatic recordings from CA1 pyramidal cells indicated a persistent upregulation of the h-current (I h ) after experimental febrile seizures.Here, we examined febrile seizure-induced long-term changes in I h and neuronal excitability in CA1 dendrites. Cell-attached recordings showed that dendritic I h was signifi cantly upregulated, with a depolarized half-activation potential and increased maximal current. Although enhanced I h is typically thought to be associated with decreased dendritic excitability, whole-cell dendritic recordings revealed a robust increase in action potential fi ring after febrile seizures. We turned to computational simulations to understand how the experimentally observed changes in I h infl uence dendritic excitability. Unexpectedly, the simulations, performed in three previously published CA1 pyramidal cell models, showed that the experimentally observed increases in I h resulted in a general enhancement of dendritic excitability, primarily due to the increased I h -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 I h in epilepsy, the enhanced I h can co-exist with, and possibly even contribute to, persistent dendritic hyperexcitability following febrile seizures in the developing hippocampus.

Effect of low frequency repetitive transcranial magnetic stimulation on kindling-induced changes in electrophysiological properties of rat CA1 pyramidal neurons

“…However, the role of HCN disorders in epilepsy is complex. Studies in experimental models indicate that both up-regulation (Dyhrfjeld-Johnsen et al, 2008;Gill et al, 2006) and down-regulation (Powell et al, 2008;Richichi et al, 2008;Santoro et al, 2010;Shah et al, 2004;Strauss et al, 2004) of HCN channels can be associated with seizures. Our Q5 data were clearly inconsistent with an increase in I h current during the neuronal hyperexcitability in CA1 region of the hippocampus.…”

Understanding effects on excitability of simulated I h modulation in simple neuronal models

“…Of particular interest is the contribution of these different effects as neuronal excitability is probed when membrane potentials are held at common levels. Holding membrane potentials at common hyperpolarized levels has been suggested as a way to compensate for changes in resting membrane potentials with I h up-regulation (Rosenkranz and Johnston 2006;Dyhrfjeld-Johnsen et al 2008). Our modeling results suggest that, although holding potentials at common levels can bring modulated neurons to within equal voltage differences from their voltage firing thresholds, this protocol may exaggerate the excitability-depressing shunting effect caused by changes in input resistances with I h up-regulation.…”

“…Another possible limitation of our simple compartmental models is that they do not accurately capture the spatial distribution of h channels or neuron morphology that may be influencing the effects of I h up-regulation. This possibility is supported by computational modeling results reported by Dyhrfjeld-Johnsen et al (2008) in their investigation of up-regulation of I h in dendrites of hippocampal pyramidal cells following febrile seizures. They compared the excitability of three different, multi-compartmental, morphologically accurate CA1 pyramidal neuron models when up-regulation of dendritic I h was simulated in a manner suggested by their experimental recordings.…”

“…3.3 Probing excitability when membrane potentials are held at common levels Some recent experimental studies investigating modulation of I h in cortical and hippocampal pyramidal neurons have considered effects on excitability by injecting depolarizing current pulses when membrane potentials are held at constant hyperpolarized levels by constant offset currents (Rosenkranz and Johnston 2006;Dyhrfjeld-Johnsen et al 2008). By maintaining common potential levels, the differences in resting membrane potentials may appear to be compensated for, since the difference between the holding potential and the voltage threshold for firing would be roughly identical even though I h regulation levels may differ.…”

Novel Etiological and Therapeutic Strategies for Neurodiseases: Mechanisms and Consequences of Febrile Seizures: Lessons From Animal Models

“…Importantly, in pyramidal cells from eFS rats, a short train of inhibitory postsynaptic potentials (IPSPs) (6 IPSPs at 50 Hz), which resembled those that occur spontaneously during the θ rhythm in vivo, but not single IPSPs, triggered post-inhibitory rebound depolarization and firing, phenomena abolished by the selective HCN blocker ZD-7288. Recently, from both whole-cell dendritic recordings and computer models of CA1 pyramidal cells, Dyhrfjeld-Johnsen et al have further confirmed the upregulation of dendritic I h in eFS rats leading to persistent dendritic hyperexcitability, primarily due to increased I h -induced depolarization of the resting membrane potential (84). Thus, it is likely that the conjunction of the potentiation of inhibitory inputs and the frequency-dependent modified I h -mediated events generated persistent hyperexcitable foci in the hippocampus following FS.…”