Axon initial segments: diverse and dynamic neuronal compartments

Abstract

The axon initial segment (AIS) is a structurally and molecularly unique neuronal compartment of the proximal axon that functions as both a physiological and physical bridge between the somatodendritic and axonal domains. The AIS has two main functions: to initiate action potentials and to maintain neuronal polarity. The cytoskeletal scaffold ankyrinG is responsible for these functions and clusters ion channels at the AIS. Recent studies reveal how the AIS forms and remarkable diversity in its structure, function, and composition that may be modulated by neuronal activity and posttranslational modifications of AIS proteins. Furthermore, AIS proteins have been implicated in a variety of human diseases. Here, we discuss these findings and what they teach us about the dynamic AIS.

Figure 1

The axon initial segment (AIS) in the most proximal part of the axon. (a) Schema of a neuron with a myelinated axon. Specific types of ion channels, receptors, adhesion molecules and molecular scaffolds are enriched in both the AIS and nodes of Ranvier. (b) Establishment of neuronal polarity in cultured hippocampal neurons. Cultured pyramidal neurons from a rodent hippocampus acquire their characteristic polarized morphology in five successive stages. The first step in neuronal polarization is initial axon formation in the transition from stage 2 to stage 3. The AIS is formed from stage 3 to stage 4. The AIS maintains neuronal polarity and regulates action potential initiation.

Figure 2

The formation and plasticity of the AIS. (a) After the axon specification, an AnkB/αII-spectrin/βII-spectrin-based distal cytoskeleton is assembled in the distal axon and progressively fills the axon toward the cell body. Later expression of AnkG and exclusion from the distal axonal cytoskeleton results in the accumulation of AnkG in the remaining proximal axon that becomes the AIS. (b) The AIS is a new target of intrinsic plasticity. In neurons from the nucleus magnocellularis of chicks, auditory deprivation leads to an increase in AIS length and increased neuronal excitability (i). The AIS is longer in a mouse model of Angelman syndrome (ii). Overexpression of AnkG induces a longer AIS in cultured neurons (iii). Exposure to a single blast wave decreases AIS length in rats (iv). AIS length is decreased within the peri-infarct cortex after white matter stroke in mice (v). Overexpression of AnkB induces a shorter AIS in cultured neurons (vi). Increased neuronal activity shifts AIS location and leads to reduced neuronal excitability (vii). (c) Loss of the intra-axonal boundary by disruption of the distal axonal cytoskeleton blocks AIS assembly and permits AnkG to be found in the distal axon.

Figure 3

Dynamic regulation of AIS proteins. Neuronal activity can ‘tune’ AIS structure, and vice versa. Post-translational modifications (e.g. phosphorylation) of AIS proteins may play key roles to modulate AIS assembly, structure and function.