Reemerging role of cable properties in action potential initiation

Abstract

It is generally accepted that the axon initial segment (AIS), the neuroanatomical region linking cell body and axon, is the site of action potential (AP) generation in central neurons (1, 2). Because the occurrence, timing, and pattern of APs play critical roles in sensory encoding, motor output, and synaptic plasticity, the mechanisms underlying AP initiation are of fundamental interest. APs are initiated through membrane depolarization driven by the influx of sodium ions (Na+) through voltage-gated ion channels. The ability of Na currents to produce local depolarization depends on the ratio of the sources and sinks of current flow. Cable theory accounts for current flow down two distinct paths: (i) longitudinally along the central conductor and (ii) transversely through the cable sheathing or membrane. This theory, initially developed to understand signal losses in transatlantic telegraph cables, is also highly applicable to neuronal membrane compartments, such as axons, dendrites, and cell bodies (3, 4). For AP initiation, the source is Na current, and the sink is the loading resulting from current flow to adjacent membrane compartments, with both resistive and capacitive passive components. According to cable theory, either greater Na+ influx or lower passive load would increase membrane depolarization and favor local initiation. To date, the role of electrical load has been inferred from the results of computational studies, with little direct support (5⇓–7). In contrast, recent studies on AP initiation have focused on differences in the localized influx of Na currents. According to this view, a region of concentrated local Na+ influx endows the AIS initiation site with the lowest AP threshold. To evaluate the relative contributions of current source and electrical load in AP initiation, it is pivotal to determine whether the AP initiation site is the location of highest Na current …