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The axon initial segment and the maintenance of neuronal polarity

Nature Reviews Neuroscience volume 11, pages 552562 (2010) | Download Citation


Ion channel clustering at the axon initial segment (AIS) and nodes of Ranvier has been suggested to be a key evolutionary innovation that enabled the development of the complex vertebrate nervous system. This innovation epitomizes a signature feature of neurons, namely polarity. The mechanisms that establish neuronal polarity, channel clustering and axon–dendrite identity during development are becoming clearer. However, much less is known about how polarity is maintained throughout life. Here, I review the role of the AIS in the development and maintenance of neuronal polarity and discuss how disrupted polarity may be a common component of many diseases and injuries that affect the nervous system.

Key points

  • The axon initial segment (AIS) functions as both a structural and a functional bridge between neuronal input and output. The AIS is characterized by clustered voltage-gated Na+ and K+ channels that integrate synaptic inputs and initiate action potentials. The AIS also has high densities of cell adhesion molecules, signalling proteins and cytoskeletal proteins and scaffolds.

  • The AIS regulates three kinds of neuronal polarity: functional polarity (that is, the directional propagation of information), anatomical polarity (that is, the distinction between axonal and somatodendritic domains) and subcellular polarity (that is, the restricted localization of ion channels, organelles and protein complexes to distinct membrane domains or cellular compartments).

  • The assembly of the AIS protein complexes and establishment of AIS subcellular polarity depends on the cytoskeletal scaffolding protein ankyrin G (AnkG, also known as ANK3). Thus, AnkG is the master organizer of the AIS.

  • The maintenance of neuronal polarity depends on a physical barrier that is located at the AIS and restricts lipids, membrane and cytoplasmic proteins and vesicular cargoes to somatodendritic or axonal domains. Actin, microtubules and the high density of proteins at the AIS all contribute to this barrier. AnkG is also required for the functioning of the barrier, including the regulation of actin and microtubules and protein retention at the AIS. Loss of AnkG results in dismantling of the AIS and the axon acquiring the structural and molecular properties of dendrites.

  • The AIS cytoskeleton can be disrupted by diseases and injuries, causing loss of clustered ion channels and anatomical polarity. Loss of neuronal polarity may be a previously overlooked consequence of nervous system injury.

  • The AIS can be viewed as the 'gatekeeper' of nervous system function, and the modulation of AIS properties can have dramatic consequences for neuronal excitability and circuit properties. Neuronal activity can modulate the location of the AIS, which in turn influences the input–output response of the neuron. In contrast to synaptic plasticity, AIS plasticity occurs over hours and even days, and therefore may result in changes to the neuronal input–output function that persist over long periods of time.

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I thank members of my laboratory both past and present for contributing to the ideas and work described here. I apologize to my colleagues for the omission of many relevant and important papers due to space limitations. This work was supported by US National Institutes of Health grant NS044916. M.N.R. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society.

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  1. Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030, USA.

    • Matthew N. Rasband


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The author declares no competing financial interests.

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Correspondence to Matthew N. Rasband.


Axon initial segment

The area of the axon near the soma that contains a high density of voltage-gated sodium channels, which are responsible for the initial depolarization that leads to the initiation of the action potential.

Nodes of Ranvier

Interruptions in the myelin sheath that covers axons. Nodes of Ranvier are enriched in Na+ channels and facilitate the propagation of action potentials by saltatory conduction.

Paranodal junctions

Major sites of physical interaction between myelin-forming glial cells and the axon. They are located on either side of the nodes of Ranvier and are characterized by septate-like junctions.


Regions beneath the myelin sheath and flanking each node of Ranvier where voltage-gated K+ channels are clustered.

Interaural time difference

The time difference for the arrival of a sound between two ears.

Coincidence detection

A mechanism whereby neurons encode information by detecting two simultaneous inputs from distinct sources.

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