Maintenance of neuronal polarity

Abstract

Neurons are highly polarized cells with distinct domains responsible for receiving, transmitting, and propagating electrical signals. Central to these functions is the axon initial segment (AIS), a short region of the axon adjacent to the cell body that is enriched in voltage-gated ion channels, cell adhesion molecules, and cytoskeletal scaffolding proteins. Traditionally, the function of the AIS has been limited to its role in action potential initiation and modulation. However, recent experiments indicate that it also plays essential roles in neuronal polarity. Here, we review how initial segments are assembled, and discuss proposed mechanisms for how the AIS contributes to maintenance of neuronal polarity.

Figure 1

The axon initial segment (AIS) is highly enriched in ion channels and cytoskeletal and scaffolding proteins. A, Cultured hippocampal neurons immunostained using antibodies against ankyrinG (green), Na+ channels (Pan Nav, red), and the somatodendritic marker MAP2 (microtubule associated protein 2; blue). B, Cortex from rat brain immunostained for the cytoskeletal scaffolding protein βIV spectrin (green), the Na+ channel accessory protein FGF14 (red), and Hoechst to indicate nuclei (blue). Image was kindly provided by Ms. Kelli Baalman. Scale bars, A, 20 μm; B, 25 μm.

Figure 2

Assembly, maintenance, and plasticity of the AIS. A, During early development neurons become polarized with an axon and somatodendritic domain. This is accompanied by the redistribution of proteins into distinct cellular compartments. After axon specification, ankG becomes restricted to the AIS (i), where it functions as a scaffold to which many other AIS proteins become attached (ii). Upon assembly of the AIS, MAP2 (blue) becomes excluded from the distal axon. B, Actin and ankyrinG play key roles in maintaining neuronal polarity and restricting membrane proteins to either axonal or somatodendritic domains. (i) Loss of actin results in mixing of membrane proteins and loss of the cytoplasmic filter, permitting somatodendritic cargoes (yellow) to enter the axon. (ii) Loss of ankG causes the former axon to dedifferentiate and acquire many of the structural and molecular characteristics of a dendrite, including MAP2 and spines with post-synaptic densities (orange). C, Disease or injury causes influx of Ca2+ which activates the protease calpain (scissors). (i) Calpain cleaves the AIS cytoskeletal proteins ankG and βIV spectrin, (ii) leading to loss of neuronal polarity. D, The AIS can be plastic under different conditions of activity. (i) Under conditions of chronic activity, the AIS can translocate to more distal regions of the axon, thereby increasing threshold for action potential initiation. (ii) Under conditions where activity is lost, the AIS can expand and become larger, making it easier for the neuron to reach threshold and fire an action potential.