Modeling HCN Channel Modulation on Dendro-Somatic Electric Coupling in CA1 Pyramidal Cells

Abstract

Introduction

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is thought to play a key role in the modulation of dendritic and somatic excitability in neurons [1]. The enigmatic HCN channel, enigmatic because of the long puzzling relation between HCN expression and neural function [1], has an inhomogeneous distribution along the somato-dendritic axis, where the density is higher in distal dendritic compartments [1]. In this modeling project, we studied the influence of HCN channel density distribution on the attenuation of current injection from the bifurcation point of the dendritic tuft in the hippocampal CA1 pyramidal cell. For that, we used a recently established reduced-morphology model of the CA1 pyramidal neuron [2]. In particular, we were interested in the electric coupling and decoupling of the apical dendritic compartment from the somatic compartment and in the modulation of this coupling by the HCN channel. 

Methodology

In all simulations, the NEURON simulation software was used. Simulated data were analyzed using Python. We injected currents using NEURON's IClamp mechanism and recorded the spread of the corresponding voltage change toward the cell's soma. We used this simple simulation setting to assess the dendro-somatic transfer of locally induced voltage perturbation.  We tested the dendro-somatic current transfer for five different HCN conductance (i.e. density) values and different current injection amplitudes ranging from subthreshold to suprathreshold for dendritic spikes. All current injections were subthreshold for somatic spikes. We compared simulations using different HCN conductance values with a virtual HCN knockout simulation representing a complete deletion of HCN channels. In addition, we varied the distance of the location of the current injection along the somato-dendritic axis to investigate the spatial dependence of HCN-modulated dendro-somatic coupling. Finally, we have varied the somato-dendritic gradient of the HCN channels [3] to estimate whether the spatially inhomogeneous distribution of the HCN conductance affects the dendro-somatic coupling.

Results

Our simulations showed that HCN channels depressed the dendro-somatic transfer of voltage changes induced by the local current injection in the CA1 pyramidal cell model, contributing to the attenuation of the signal.  Our computational model indicates that HCN conductance contributes to the linearization of the dependence of somatic voltage responses on the increasing amplitude of the dendritic current injection. In addition, in line with previous literature [1, 3] we observed that HCN channels depolarized the resting potential of pyramidal neurons. In conclusion, we have confirmed that HCN channels affect both the dendro-somatic transfer of voltage changes induced by local current injection as well as resting potential.

Discussion

In this project, we have studied the effects of the HCN channel on the electrophysiological behavior of a neuron model that was activated by increasing current steps. This electrophysiological behavior should be studied under more natural stimulation conditions such as activation of dendritic synapses. In addition, future simulations should address the complex interactions of dendritic and somatic spikes and their relevance for spatial processing in CA1 pyramidal cells. Finally,  rather than studying the effects of HCN channel changes in isolation, we should explore their effects in the context of a plethora of co-expressing ion channels, which might reveal heterogeneity of their electrophysiological effects.

References

[1] P. Mishra and R. Narayanan, “The enigmatic HCN channels: A cellular neurophysiology perspective,” Proteins, p. prot.26643, Nov. 2023, doi: 10.1002/prot.26643

[2] M. Tomko, L. Benuskova, and P. Jedlicka, “A new reduced-morphology model for CA1 pyramidal cells and its validation and comparison with other models using HippoUnit,” Sci Rep, vol. 11, no. 1, p. 7615, Apr. 2021, doi: 10.1038/s41598-021-87002-7.

[3] K. Angelo, M. London, S. R. Christensen, and M. Häusser, “Local and Global Effects of I _h Distribution in Dendrites of Mammalian Neurons,” J. Neurosci., vol. 27, no. 32, pp. 8643–8653, Aug. 2007, doi: 10.1523/JNEUROSCI.5284-06.2007.