Axon initial segments: structure, function, and disease

Abstract

The axon initial segment (AIS) is located at the proximal axon and is the site of action potential initiation. This reflects the high density of ion channels found at the AIS. Adaptive changes to the location and length of the AIS can fine-tune the excitability of neurons and modulate plasticity in response to activity. The AIS plays an important role in maintaining neuronal polarity by regulating the trafficking and distribution of proteins that function in somatodendritic or axonal compartments of the neuron. In this review, we provide an overview of the AIS cytoarchitecture, mechanism of assembly, and recent studies revealing mechanisms of differential transport at the AIS that maintain axon and dendrite identities. We further discuss how genetic mutations in AIS components (i.e., ankyrins, ion channels, and spectrins) and injuries may cause neurological disorders.

Keywords: axon; cytoskeleton; ion channel; polarity.

Figure 1

Cartoon of a multipolar neuron and the molecular composition of the AIS. (A) Neurons are polarized into somatodendritic and axonal domains. Axons can be myelinated by oligodendrocytes in the CNS and Schwann cells in the PNS. Nodes of Ranvier are gaps in the myelin sheath. Both axon initial segments and nodes of Ranvier have high densities of Na⁺ channels for action potential initiation and propagation, respectively. (B) The molecular organization of the axon initial segment.

Figure 2

Axon initial segments in health and disease. (A) A cultured hippocampal neuron immunolabeled using antibodies against βIV spectrin (red), Trim46 (green), and MAP2 (blue). Scalebar = 10 μm. (B) A cultured hippocampal neuron infected with virus to express GFP and ankG shRNA. The neuron has lost neuronal polarity; the former axon (arrows) acquires dendritic features including MAP2 and spines (box and inset). Scalebar = 20 μm. Modified from Hedstrom et al. (C) Na⁺ channels are lost from the AIS following ischemic injury. Contralateral (left) and ipsilateral (right) regions of rat cortex were immunolabelled for Na+ channels (PanNav, red), ankG (green), and Hoechst to label nuclei (blue). The sections shown are from a brain collected 24 hr after MCAO. Arrows indicate labeled AIS in layer 2/3 cortex. Scale bar = 50 μm. Modified from Schafer et al.