Density Of Voltage-gated Channels Research Articles

Modeling interneuron-specific (IS) interneurons in hippocampus

The hippocampus and cortex have a large diversity in inhibitory interneuron types. These local interneurons exert inhibitory control over neuronal populations in the hippocampus [1]. Although much is known about how hippocampal inhibitory interneurons exert control over pyramidal cells and synchronize local network activity, less is known about how the activity of these interneurons are controlled themselves. Moreover, the existence of interneuron-specific (IS) interneurons is known and information about how these IS interneurons exert their influence is accumulating [2]. In particular, interneuron-specific 3 (IS3) cells are being characterized and they have been shown to primarily synapse onto other interneuron dendrites with the ability to control their firing patterns. Morphological and synaptic aspects are being examined, but what type, how much and where voltage-gated channels are present on IS3 has not been determined. As other hippocampal interneuron types are known to have high densities of voltage-gated channels on their dendrites [3,4], it seems likely that this could be the case for IS3 cells also. Determining and understanding particular characteristics of particular cell types is a highly challenging endeavour using purely experimental means. Thus, we have begun development of IS3 computational cell models to help address this challenge. Using the NEURON software environment [5], we have reconstructed IS3 cell morphologies and built multi-compartment models from them in which appropriate passive properties were obtained. Further, we were able to match several characteristics of representative IS3 cell firings (spike amplitude, spike threshold, rheobase) using four somatically located voltage-gated channel types (sodium current (INa), slow delayed rectifier potassium current (IKdrs), fast delayed rectifier potassium current (IKdrf) and A-type potassium current (IKa). Preliminary data from IS3 cells indicate that they express intrinsic, subthreshold activities similar to other hippocampal interneuron types [6], and previous models captured this aspect with the incorporation of additive white noise to represent stochastic gating characteristics [7]. Similarly here, to capture these aspects, we somatically injected white noise current into our models and found that output similar to experimental data was observed. Given the present correspondence with data, our models already make predictions about channel types and balances found in IS3 cells. Thus our present multi-compartment IS3 models represent a solid basis for determining and understanding the biophysical contributions for IS3 cell firings and their ability to control inhibitory cells and functionally contribute to the generation of hippocampal oscillations.

Influence of asymmetric attenuation of single and paired dendritic inputs on summation of synaptic potentials and initiation of action potentials

Previous studies revealed mechanisms of dendritic inputs leading to action potential initiation at the axon initial segment and backpropagation into the dendritic tree. This interest has recently expanded toward the communication between different parts of the dendritic tree which could preprocess information before reaching the soma. This study tested for effects of asymmetric voltage attenuation between different sites in the dendritic tree on summation of synaptic inputs and action potential initiation using the NEURON simulation environment. Passive responses due to the electrical equivalent circuit of the three-dimensional neuron architecture with leak channels were examined first, followed by the responses after adding voltage-gated channels and finally synaptic noise. Asymmetric attenuation of voltage, which is a function of asymmetric input resistance, was seen between all pairs of dendritic sites but the transfer voltages (voltage recorded at the opposite site from stimulation among a pair of dendritic sites) were equal and also summed linearly with local voltage responses during simultaneous stimulation of both sites. In neurons with voltage-gated channels, we reproduced the observations where a brief stimulus to the proximal ascending dendritic branch of a pyramidal cell triggers a local action potential but a long stimulus triggers a somal action potential. Combined stimulation of a pair of sites in this proximal dendrite did not alter this pattern. The attraction of the action potential onset toward the soma with a long stimulus in the absence of noise was due to the higher density of voltage-gated sodium channels at the axon initial segment. This attraction was, however, negligible at the most remote distal dendritic sites and was replaced by an effect due to high input resistance. Action potential onset occurred at the dendritic site of higher input resistance among a pair of remote dendritic sites, irrespective of which of these two sites received the synaptic input. Exploration of the parameter space showed how the gradient of voltage-gated channel densities and input resistances along a dendrite could draw the action potential onset away from the stimulation site. The attraction of action potential onset toward the higher density of voltage-gated channels in the soma during stimulation of the proximal dendrite was, however, reduced after the addition of synaptic noise.

Ion channel density and threshold dynamics of repetitive firing in a cortical neuron model

Modifying the density and distribution of ion channels in a neuron (by natural up- and down-regulation, by pharmacological intervention or by spontaneous mutations) changes its activity pattern. In the present investigation, we analyze how the impulse patterns are regulated by the density of voltage-gated channels in a model neuron, based on voltage clamp measurements of hippocampal interneurons. At least three distinct oscillatory patterns, associated with three distinct regions in the Na–K channel density plane, were found. A stability analysis showed that the different regions are characterized by saddle-node, double-orbit, and Hopf bifurcation threshold dynamics, respectively. Single strongly graded action potentials occur in an area outside the oscillatory regions, but less graded action potentials occur together with repetitive firing over a considerable range of channel densities. The presently found relationship between channel densities and oscillatory behavior may be relevance for understanding principal spiking patterns of cortical neurons (regular firing and fast spiking). It may also be of relevance for understanding the action of pharmacological compounds on brain oscillatory activity.

Channel Density Regulation of Firing Patterns in a Cortical Neuron Model

Modifying the density and distribution of ion channels in a neuron (by natural up- and downregulation or by pharmacological intervention or by spontaneous mutations) changes its activity pattern. In this investigation we analyzed how the impulse patterns are regulated by the density of voltage-gated channels in a neuron model based on voltage-clamp measurements of hippocampal interneurons. At least three distinct oscillatory patterns, associated with three distinct regions in the Na-K channel density plane, were found. A stability analysis showed that the different regions are characterized by saddle-node, double-orbit, and Hopf-bifurcation threshold dynamics, respectively. Single, strongly graded action potentials occur in an area outside the oscillatory regions, but less graded action potentials occur together with repetitive firing over a considerable range of channel densities. The relationship found here between channel densities and oscillatory behavior may partly explain the difference between the principal spiking patterns previously described for crab axons (class 1 and 2) and cortical neurons (regular firing and fast spiking).