HYPERPOLARIZED VIEWS ON THE ROLES OF THE HYPERPOLARIZATION-ACTIVATED CHANNELS IN NEURONAL EXCITABILITY

Upregulated H-Current in Hyperexcitable CA1 Dendrites after Febrile Seizures. Dyhrfjeld-Johnsen J, Morgan RJ, Csaba Foldy, Soltesz I., Front Cell Neurosci. 2008; 2: 2. doi: 10.3389/neuro.03.002.2008. Somatic recordings from CA1 pyramidal cells indicated a persistent upregulation of the h-current (l(h)) after experimental febrile seizures. Here, we examined febrile seizure-induced long-term changes in l(h) and neuronal excitability in CA1 dendrites. Cell-attached recordings showed that dendritic l(h) was significantly upregulated, with a depolarized half-activation potential and increased maximal current. Although enhanced l(h) 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 l(h) influence dendritic excitability. Unexpectedly, the simulations, performed in three previously published CA1 pyramidal cell models, showed that the experimentally observed increases in l(h) resulted in a general enhancement of dendritic excitability, primarily due to the increased l(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 l(h) in epilepsy, the enhanced l(h) can co-exist with, and possibly even contribute to, persistent dendritic hyperexcitability following febrile seizures in the developing hippocampus. HCN Hyperpolarization-Activated Cation Channels Inhibit EPSPs by Interactions with M-type K(+) Channels. George MS, Abbott LF, Siegelbaum SA. Nat Neurosci 2009; 12(5): 577-584. The processing of synaptic potentials by neuronal dendrites depends on both their passive cable properties and active voltage-gated channels, which can generate complex effects as a result of their nonlinear properties. We characterized the actions of HCN (hyperpolarization-activated cyclic nucleotide-gated cation) channels on dendritic processing of subthreshold excitatory postsynaptic potentials (EPSPs) in mouse CA1 hippocampal neurons. The HCN channels generated an excitatory inward current (l(h)) that exerted a direct depolarizing effect on the peak voltage of weak EPSPs, but produced a paradoxical hyperpolarizing effect on the peak voltage of stronger, but still subthreshold, EPSPs. Using a combined modeling and experimental approach, we found that the inhibitory action of l(h) was caused by its interaction with the delayed-rectifier M-type K+ current. In this manner, l(h) can enhance spike firing in response to an EPSP when spike threshold is low and can inhibit firing when spike threshold is high.