Spatial mismatch between the Na ⁺ flux and spike initiation in axon initial segment

Abstract

It is widely believed that, in cortical pyramidal cells, action potentials (APs) initiate in the distal portion of axon initial segment (AIS) because that is where Na + channel density is highest. To investigate the relationship between the density of Na + channels and the spatiotemporal pattern of AP initiation, we simultaneously recorded Na + flux and action currents along the proximal axonal length. We found that functional Na + channel density is approximately four times lower in the AP trigger zone than in the middle of the AIS, where it is highest. Computational analysis of AP initiation revealed a paradoxical mismatch between the AP threshold and Na + channel density, which could be explained by the lopsided capacitive load imposed on the proximal end of the AIS by the somatodendritic compartment. Favorable conditions for AP initiation are therefore achieved in the distal AIS portion, close to the edge of myelin, where the current source-load ratio is highest. Our findings suggest that cable properties play a central role in determining where the AP starts, such that small plastic changes in the local AIS Na + channel density could have a large influence on neuronal excitability as a whole.neocortex | pyramidal neuron | sodium imaging I n cortical pyramidal cells, as in many CNS neurons, action potentials (APs) generally initiate in the axon initial segment (AIS) (refs. 1-4; reviewed in ref. 5), the proximal part of the axon where the neuronal membrane is not covered with a myelin sheath, and which possesses a distinctive, specialized assembly of voltage-gated channels and associated proteins (6). Because of the pivotal role that the AIS plays in transformation of synaptic input into AP output, precise characterization of its excitable properties is essential for a complete understanding of the cellular mechanisms that underlie operation of cortical neurons and networks. Early theoretical studies proposed two mechanisms to explain preferential AIS AP initiation (7, 8): (i) less current is required to depolarize the AIS membrane to threshold because it is electrically isolated from the neighboring neuronal compartments, and (ii) the depolarizing current density is higher in the AIS than in neighboring compartments, allowing the AIS to overcome their electric load. These two mechanisms are not mutually exclusive, but the technical difficulties that hinder precise measurements in thin neuronal processes have made it difficult to elucidate their relative importance for AP initiation.During the past decade, the isolation hypothesis has been addressed by only a few studies (9), and values of the relevant resistances and capacitances are only approximations. By contrast, the findings by many groups that Na + channel density is relatively high in the proximal axon have focused most attention on the higher current hypothesis, although there remains some controversy as to what extent the density of functional Na + channels is greater in the AIS than in the soma (refs. 10-14; reviewed in ref. 15). The role of high ...

Polarized localization of voltage-gated Na + channels is regulated by concerted FGF13 and FGF14 action

“…In most primary neurons, efficient action potential initiation depends on the clustering of VGSCs at the axon initial segment (AIS) (2)(3)(4). VGSC density within the AIS is ∼10-to 80-fold higher than in the somatodendritic compartment (5,6), even though VGSCs are initially inserted into both somatodendritic and axonal membranes (7).…”

Reemerging role of cable properties in action potential initiation

“…Most strikingly, Baranauskas et al (8) are able to strongly dissociate the AP initiation site from the site of greatest Na + influx. According to the distribution of SBFI fluorescence intensities obtained with HSN imaging during single APs, the authors divided the entire AIS into three segments (S1-S3) (Fig.…”

“…These questions have remained unanswered, largely because of technical constraints of existing AIS recording technologies. In PNAS, Baranauskas et al (8) combine multiple experimental and theoretical approaches to address this important question and identify a key role of cable properties in determining the site of AP initiation.…”

“…The study by Baranauskas et al (8) uses a sophisticated technique, high speed Na (HSN) imaging, to directly investigate the distribution of Na current within the AIS. The basic principle of this method is to load individual neurons with a Na + -sensitive dye, sodium-binding benzofuran isophthalate (SBFI), and then to monitor changes in intraaxonal Na + concentration ([Na + ]) via changes in fluorescence.…”

A supercritical density of fast Na+ channels ensures rapid propagation of action potentials in GABAergic interneuron axons

“…Thus, APs were robustly initiated in the axon at a proximal site. This situation is different from that in glutamatergic pyramidal neurons, where the AP initiation site is more remote [15][16][17][18][19] .To probe the reliability of AP propagation, we applied high-frequency trains of brief current pulses at the soma (120 APs at 100 Hz; Fig. 2d-f).…”