Function of Specific K⁺ Channels in Sustained High-Frequency Firing of Fast-Spiking Neocortical Interneurons

Abstract

Fast-spiking GABAergic interneurons of the neocortex and hippocampus fire high-frequency trains of brief action potentials with little spike-frequency adaptation. How these striking properties arise is unclear, although recent evidence suggests K(+) channels containing Kv3.1-Kv3.2 proteins play an important role. We investigated the role of these channels in the firing properties of fast-spiking neocortical interneurons from mouse somatosensory cortex using a pharmacological and modeling approach. Low tetraethylammonium (TEA) concentrations (</=1 mM), which block only a few known K(+) channels including Kv3.1-Kv3.2, profoundly impaired action potential repolarization and high-frequency firing. Analysis of the spike trains evoked by steady depolarization revealed that, although TEA had little effect on the initial firing rate, it strongly reduced firing frequency later in the trains. These effects appeared to be specific to Kv3.1 and Kv3.2 channels, because blockade of dendrotoxin-sensitive Kv1 channels and BK Ca(2+)-activated K(+) channels, which also have high TEA sensitivity, produced opposite or no effects. Voltage-clamp experiments confirmed the presence of a Kv3.1-Kv3.2-like current in fast-spiking neurons, but not in other interneurons. Analysis of spike shape changes during the spike trains suggested that Na(+) channel inactivation plays a significant role in the firing-rate slowdown produced by TEA, a conclusion that was supported by computer simulations. These findings indicate that the unique properties of Kv3.1-Kv3.2 channels enable sustained high-frequency firing by facilitating the recovery of Na(+) channel inactivation and by minimizing the duration of the afterhyperpolarization in neocortical interneurons.

Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1

“…Given the diversity of voltage-gated ion channels (143 channel genes in the human genome (1)), it is of general interest to consider what constitutes the variability and what functional role it plays in forming and regulating neuronal firing patterns (2)(3)(4)(5)(6)(7)(8)(9)(10). The basic functional channel parameters are ion selectivity and gating, the latter characterized by opening/closing kinetics and the voltage dependence of the channel's open probability.…”

The robustness of phase-locking in neurons with dendro-dendritic electrical coupling

“…In all the simulations presented here, we use the fast-spiking (FS) interneuron model of Erisir et al (1999). However, the basic analysis that we employ is general and can be applied to any oscillatory somatic dynamics with similar results.…”

“…For reference, Fig. 2 plots the voltage component of the limit cycle and the corresponding phase response curve of the FS interneuron model of Erisir et al (1999) for the two different firing frequencies that we utilize in illustrating our results. The integral in the phase model (8) is the average of Z (s)I coupl (s; T (φ k − φ j )) over one period of the oscillations and stems from the fact that changes in the relative phase of the neuron φ j occur on a time scale much slower than the period of the unperturbed oscillations T .…”

“…However, we stress that our basic results do not fundamentally depend on the specifics of the somatic dynamics. In all figures, we use a model for neocortical FS interneurons due to Erisir et al (1999) to model the somatic firing dynamics. The values for the parameters of this model as well as dendritic parameters that are held constant are detailed in the Appendix A.…”

“…We used a model of a cortical inhibitory fast spiking interneuron due to Erisir et al (1999) to describe our somatic dynamics. The model equations and parameters are…”