SingleI_hChannels in Pyramidal Neuron Dendrites: Properties, Distribution, and Impact on Action Potential Output

Abstract

The hyperpolarization-activated cation current (I h ) plays an important role in regulating neuronal excitability, yet its native singlechannel properties in the brain are essentially unknown. Here we use variance-mean analysis to study the properties of single I h channels in the apical dendrites of cortical layer 5 pyramidal neurons in vitro. In these neurons, we find that I h channels have an average unitary conductance of 680 Ϯ 30 fS (n ϭ 18). Spectral analysis of simulated and native I h channels showed that there is little or no channel flicker below 5 kHz. In contrast to the uniformly distributed single-channel conductance, I h channel number increases exponentially with distance, reaching densities as high as ϳ550 channels/m 2 at distal dendritic sites. These high channel densities generate significant membrane voltage noise. By incorporating a stochastic model of I h single-channel gating into a morphologically realistic model of a layer 5 neuron, we show that this channel noise is higher in distal dendritic compartments and increased threefold with a 10-fold increased single-channel conductance (6.8 pS) but constant I h current density. In addition, we demonstrate that voltage fluctuations attributable to stochastic I h channel gating impact on action potential output, with greater spike-timing precision in models with the experimentally determined single-channel conductance. These data suggest that, in the face of high current densities, the small single-channel conductance of I h is critical for maintaining the fidelity of action potential output.

Dendritic HCN2 Channels Constrain Glutamate-Driven Excitability in Reticular Thalamic Neurons

“…Increased I h (Fan et al, 2005) or HCN1 channel expression (Nolan et al, 2004) decreases intrinsic and synaptic excitability through a current leak path (Robinson and Siegelbaum, 2003), which presumably occurs at the dendritic level; conversely, I h block enhances both excitability and EPSP responses, which can be attributed to an increase in R in (Magee, 1998;Williams and Stuart, 2000;Berger et al, 2001;Kole et al, 2006). Functional expression of dendritic RTN HCN2 channels appears to recapitulate many aspects of dendritic HCN1 function seen in other brain areas.…”

“…HCN channels are unevenly distributed on the cell membrane; for example, HCN1 is preferentially expressed on distal dendritic membranes of pyramidal cells in the cortex, hippocampus, and subiculum (Lörincz et al, 2002). Consistently, dendritic I h current density and amplitude increases as one moves farther away from the soma (Magee, 1998;Williams and Stuart, 2000;Berger et al, 2001;Kole et al, 2006). Dendritic I h normalizes temporal summation (Stuart and Spruston, 1998;Magee, 1999;Berger et al, 2001;Koch and Grothe, 2003), disconnects somatic and dendritic spike initiation zones (Berger et al, 2003), and likely limits the development of long-term potentiation (Nolan et al, 2004).…”

Control of layer 5 pyramidal cell spiking by oscillatory inhibition in the distal apical dendrites: a computational modeling study

“…It has been proposed (Hutcheon and Yarom 2000) that resonance in the subthreshold membrane potential occurs when the intrinsic low-pass filtering nature of the neuronal membrane is combined with currents which act as a high-pass filter. I h has been suggested to play such a role and is known to be present in distal dendrites (Berger et al 2001;Kole et al 2006;Williams and Stuart 2000). We examined whether the observed resonance of the firing rate with the frequency of distal oscillatory inhibition might be driven by such membrane potential resonance, and whether it depends on I h .…”

Advances in Understanding of Structure, Function and Plasticity of HCN Channels

“…Knockout of TRIP8b in pyramidal neuron dendrites in mice, manifests, in addition to motor learning deficits, in enhanced resistance to multiple tasks of behavioural despair, a known measure of antidepressant efficacy 37 . The single-channel conductance of HCN is very low (<1 pS), rendering single-channel recordings problematic with the current state-of-the-art in eletrophysiology 9,38 , and claims of such recordings have been controversial 39 . In our study for the same channel composition, kinetics changed with changes in intracellular signalling, indicating that like voltage of activation, kinetics can be easily modulated 40 .…”