Role of Axonal Na_V1.6 Sodium Channels in Action Potential Initiation of CA1 Pyramidal Neurons

Abstract

In many neuron types, the axon initial segment (AIS) has the lowest threshold for action potential generation. Its active properties are determined by the targeted expression of specific voltage-gated channel subunits. We show that the Na+ channel NaV1.6 displays a striking aggregation at the AIS of cortical neurons. To assess the functional role of this subunit, we used Scn8amed mice that are deficient for NaV1.6 subunits but still display prominent Na+ channel aggregation at the AIS. In CA1 pyramidal cells from Scn8amed mice, we found a depolarizing shift in the voltage dependence of activation of the transient Na+ current (INaT), indicating that NaV1.6 subunits activate at more negative voltages than other NaV subunits. Additionally, persistent and resurgent Na+ currents were significantly reduced. Current-clamp recordings revealed a significant elevation of spike threshold in Scn8amed mice as well as a shortening of the estimated delay between spike initiation at the AIS and its arrival at the soma. In combination with simulations using a realistic computer model of a CA1 pyramidal cell, our results imply that a hyperpolarized voltage dependence of activation of AIS NaV1.6 channels is important both in determining spike threshold and localizing spike initiation to the AIS. In addition to altered spike initiation, Scn8amed mice also showed a strongly reduced spike gain as expected with combined changes in persistent and resurgent currents and spike threshold. These results suggest that NaV1.6 subunits at the AIS contribute significantly to its role as spike trigger zone and shape repetitive discharge properties of CA1 neurons.

Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus

“…Two phases of initiation are revealed readily in the second derivative of the AP (d 2 V/dt 2 ; Figure 6, B and C), as described previously for other neuron types (20,21). The first phase of AP upstroke is due to spike propagation from the AIS into the soma (Figure 6B), while the second phase is caused by generation of the somatic AP ( Figure 6B) (20,21). Figure 6 illustrates a significant increase of the membrane voltage acceleration in the first peak corresponding to AP initiation in the AIS of CW neurons ( Figure 6, B, C, and E; CC, n = 103 APs, CW, n = 124; P < 0.0001).…”

“…Heterozygous mice show increased propensity to thermally triggered seizures, analogous to FS seen in human patients carrying the β1(C121W) mutation (3,4). We demonstrate that the wild-type subunit is localized to the AIS, the site of AP initiation (13,(18)(19)(20)(21), and importantly, the β1(W121) mutant is excluded from the membrane of this neuronal compartment. Current clamp recordings revealed increased excitability in neurons of mice heterozygous for the β1(C121W) mutation caused by a temperature-sensitive change in AIS function.…”

“…Because the data so far suggested that the β1(C121W) mutation gives rise to a selective change in AIS molecular composition and because the AIS is the site for AP initiation in most neurons (19)(20)(21)35), we next made a detailed examination of AP initiation. Two phases of initiation are revealed readily in the second derivative of the AP (d 2 V/dt 2 ; Figure 6, B and C), as described previously for other neuron types (20,21). The first phase of AP upstroke is due to spike propagation from the AIS into the soma (Figure 6B), while the second phase is caused by generation of the somatic AP ( Figure 6B) (20,21).…”

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

“…Persistent currents are important for the generation of repetitive firing in neurons as occurs, for example, in cerebellar Purkinje cells (23) and cultured hippocampal CA1 pyramidal cells (56). Membranes containing Nav1.6 are more excitable than those containing only Nav1.1 and Nav1.2, and loss of Nav1.6 results in a higher threshold for the initiation of action potentials (57).…”

Estimating the modulatory effects of nanoparticles on neuronal circuits using computational upscaling

“…This is consistent with the fact that the Na V isoforms in hippocampal cells (Na v 1.1 and 1.2) and in chromaffin cells (Na v 1.7) have an amino acid sequence similarity of about 95% and show nearly identical electrophysiological behavior. [23][24][25][26][27][28] We employed our findings on Na v 1.7 channels for the modeling approach, in which we devolve the measured effects of cAgNP on chromaffin cell voltage-gated sodium currents, to voltage-gated sodium channels of thalamic neurons (STC, NSTC, RTN).…”