Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The axon initial segment and the maintenance of neuronal polarity

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.

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Neurons are highly polarized cells.
Figure 2: The axon initial segment and nodes of Ranvier are prototypical examples of subcellular polarity.
Figure 3: Molecular substrates of the axon initial segment barrier.
Figure 4: Ankyrin G is required to maintain neuronal polarity.
Figure 5: Nervous system injury and disease alters neuronal polarity.

Similar content being viewed by others

References

  1. Lopez-Munoz, F., Boya, J. & Alamo, C. Neuron theory, the cornerstone of neuroscience, on the centenary of the Nobel Prize award to Santiago Ramon y Cajal. Brain Res. Bull. 70, 391–405 (2006).

    Article  PubMed  Google Scholar 

  2. Kole, M. H. et al. Action potential generation requires a high sodium channel density in the axon initial segment. Nature Neurosci. 11, 178–186 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Kole, M. H., Letzkus, J. J. & Stuart, G. J. Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron 55, 633–647 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Goldberg, E. M. et al. K+ channels at the axon initial segment dampen near-threshold excitability of neocortical fast-spiking GABAergic interneurons. Neuron 58, 387–400 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Naundorf, B., Wolf, F. & Volgushev, M. Unique features of action potential initiation in cortical neurons. Nature 440, 1060–1063 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Barnes, A. P. & Polleux, F. Establishment of axon–dendrite polarity in developing neurons. Annu. Rev. Neurosci. 32, 347–381 (2009). This excellent review provides a broad overview of the developmental mechanisms underlying the establishment of neuronal polarity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Peters, A., Palay, S. L. & Webster, H. D. The Fine Structure of the Nervous System: the Neurons and Supporting Cells (W. B. Saunders Company, Philadelphia, Pennsylvania, 1976).

    Google Scholar 

  8. Clark, B. D., Goldberg, E. M. & Rudy, B. Electrogenic tuning of the axon initial segment. Neuroscientist 15, 651–668 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Susuki, K. & Rasband, M. N. Molecular mechanisms of node of Ranvier formation. Curr. Opin. Cell Biol. 20, 616–623 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Salzer, J. L., Brophy, P. J. & Peles, E. Molecular domains of myelinated axons in the peripheral nervous system. Glia 56, 1532–1540 (2008).

    Article  PubMed  Google Scholar 

  11. Ogawa, Y. & Rasband, M. N. The functional organization and assembly of the axon initial segment. Curr. Opin. Neurobiol. 18, 307–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Hill, A. S. et al. Ion channel clustering at the axon initial segment and node of ranvier evolved sequentially in early chordates. PLoS Genet. 4, e1000317 (2008). This fascinating study reveals the evolutionary sequence of events for Na+ and K+ channel clustering at the AIS and strongly suggests that nodes of Ranvier are evolutionary derivatives of the AIS.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hu, W. et al. Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation. Nature Neurosci. 12, 996–1002 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Yang, Y., Ogawa, Y., Hedstrom, K. L. & Rasband, M. N. βIV spectrin is recruited to axon initial segments and nodes of Ranvier by ankyrinG. J. Cell Biol. 176, 509–519 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lorincz, A. & Nusser, Z. Molecular identity of dendritic voltage-gated sodium channels. Science 328, 906–909 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kole, M. H. & Stuart, G. J. Is action potential threshold lowest in the axon? Nature Neurosci. 11, 1253–1255 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Zonta, B. et al. Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system. J. Cell Biol. 181, 1169–1177 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Eshed, Y. et al. Gliomedin mediates schwann cell–axon interaction and the molecular assembly of the nodes of Ranvier. Neuron 47, 215–229 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Feinberg, K. et al. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier. Neuron 65, 490–502 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bennett, V. & Baines, A. J. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol. Rev. 81, 1353–1392 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Kordeli, E., Lambert, S. & Bennett, V. AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J. Biol. Chem. 270, 2352–2359 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Le-maillet, G., Walker, B. & Lambert, S. Identification of a conserved ankyrin-binding motif in the family of sodium channel alpha subunits. J. Biol. Chem. 278, 27333–27339 (2003).

    Article  CAS  Google Scholar 

  23. Garrido, J. J. et al. A targeting motif involved in sodium channel clustering at the axonal initial segment. Science 300, 2091–2094 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Bréchet, A. et al. Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interaction with ankyrin G. J. Cell Biol. 183, 1101–1114 (2008). This paper showed that phosphorylation of Na+ channels by CSNK2 increases Na+ channel affinity for AnkG at nodes and the AIS. It also suggests that the density of channels at the AIS and nodes could by regulated by phosphorylation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Fache, M. P. et al. Endocytotic elimination and domain-selective tethering constitute a potential mechanism of protein segregation at the axonal initial segment. J. Cell Biol. 166, 571–578 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhou, D. et al. AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J. Cell Biol. 143, 1295–1304 (1998). This paper was the first to show that AnkG is required for Na+ channel clustering at the AIS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hedstrom, K. L. et al. Neurofascin assembles a specialized extracellular matrix at the axon initial segment. J. Cell Biol. 178, 875–886 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pan, Z. et al. A common ankyrin-G-based mechanism retains KCNQ and Nav channels at electrically active domains of the axon. J. Neurosci. 26, 2599–2613 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jenkins, S. M. & Bennett, V. Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments. J. Cell Biol. 155, 739–746 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Berghs, S. et al. βIV spectrin, a new spectrin localized at axon initial segments and nodes of ranvier in the central and peripheral nervous system. J. Cell Biol. 151, 985–1002 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Van Wart, A., Trimmer, J. S. & Matthews, G. Polarized distribution of ion channels within microdomains of the axon initial segment. J. Comp. Neurol. 500, 339–352 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Boiko, T. et al. Ankyrin-dependent and -independent mechanisms orchestrate axonal compartmentalization of L1 family members neurofascin and L1/neuron-glia cell adhesion molecule. J. Neurosci. 27, 590–603 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, X. & Bennett, V. Restriction of 480/270-kD ankyrin G to axon proximal segments requires multiple ankyrin G-specific domains. J. Cell Biol. 142, 1571–1581 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schultz, C. et al. Coincident enrichment of phosphorylated IκBα, activated IKK, and phosphorylated p65 in the axon initial segment of neurons. Mol. Cell. Neurosci. 33, 68–80 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Sanchez-Ponce, D., Tapia, M., Munoz, A. & Garrido, J. J. New role of IKK α/β phosphorylated IκBα in axon outgrowth and axon initial segment development. Mol. Cell. Neurosci. 37, 832–844 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Arimura, N. & Kaibuchi, K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nature Rev. Neurosci. 8, 194–205 (2007).

    Article  CAS  Google Scholar 

  37. Kobayashi, T., Storrie, B., Simons, K. & Dotti, C. G. A functional barrier to movement of lipids in polarized neurons. Nature 359, 647–650 (1992).

    Article  CAS  PubMed  Google Scholar 

  38. Nakada, C. et al. Accumulation of anchored proteins forms membrane diffusion barriers during neuronal polarization. Nature Cell Biol. 5, 626–632 (2003). These authors showed that the diffusion of single phospholipids was impeded in the AIS and that during development this corresponded to the time at which the AIS formed.

    Article  CAS  PubMed  Google Scholar 

  39. Winckler, B., Forscher, P. & Mellman, I. A diffusion barrier maintains distribution of membrane proteins in polarized neurons. Nature 397, 698–701 (1999). The experiments reported here showed the existence of a membrane protein diffusion barrier at the AIS that depends on actin.

    Article  CAS  PubMed  Google Scholar 

  40. Song, A. H. et al. A selective filter for cytoplasmic transport at the axon initial segment. Cell 136, 1148–1160 (2009). This paper showed the existence of an actin-dependent cytoplasmic diffusion barrier at the AIS.

    Article  CAS  PubMed  Google Scholar 

  41. Lemmon, M. A., Ferguson, K. M. & Abrams, C. S. Pleckstrin homology domains and the cytoskeleton. FEBS Lett. 513, 71–76 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Yang, Y., Lacas-Gervais, S., Morest, D. K., Solimena, M. & Rasband, M. N. βIV spectrins are essential for membrane stability and the molecular organization of nodes of Ranvier. J. Neurosci. 24, 7230–7240 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Komada, M. & Soriano, P. βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J. Cell Biol. 156, 337–348 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ren, Q. & Bennett, V. Palmitoylation of neurofascin at a site in the membrane-spanning domain highly conserved among the L1 family of cell adhesion molecules. J. Neurochem. 70, 1839–1849 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Ogawa, Y. et al. Postsynaptic density-93 clusters Kv1 channels at axon initial segments independently of Caspr2. J. Neurosci. 28, 5731–5739 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. El-Husseini, A. E. et al. Ion channel clustering by membrane-associated guanylate kinases. Differential regulation by N-terminal lipid and metal binding motifs. J. Biol. Chem. 275, 23904–23910 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. el-Husseini Ael, D. & Bredt, D. S. Protein palmitoylation: a regulator of neuronal development and function. Nature Rev. Neurosci. 3, 791–802 (2002).

    Article  CAS  Google Scholar 

  48. Colbert, C. M. & Johnston, D. Axonal action-potential initiation and Na+ channel densities in the soma and axon initial segment of subicular pyramidal neurons. J. Neurosci. 16, 6676–6686 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Colbert, C. M. & Pan, E. Ion channel properties underlying axonal action potential initiation in pyramidal neurons. Nature Neurosci. 5, 533–538 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Nishimura, K., Akiyama, H., Komada, M. & Kamiguchi, H. βIV-spectrin forms a diffusion barrier against L1CAM at the axon initial segment. Mol. Cell. Neurosci. 34, 422–430 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Hedstrom, K. L., Ogawa, Y. & Rasband, M. N. AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity. J. Cell Biol. 183, 635–640 (2008). This paper was the first to demonstrate that the AIS diffusion barrier and maintenance of neuronal polarity depend on AnkG.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. John, N. et al. Brevican-containing perineuronal nets of extracellular matrix in dissociated hippocampal primary cultures. Mol. Cell. Neurosci. 31, 774–784 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Dzhashiashvili, Y. et al. Nodes of Ranvier and axon initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J. Cell Biol. 177, 857–870 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sobotzik, J. M. et al. AnkyrinG is required to maintain axo-dendritic polarity in vivo. Proc. Natl Acad. Sci. USA 106, 17564–17569 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Palay, S. L., Sotelo, C., Peters, A. & Orkand, P. M. The axon hillock and the initial segment. J. Cell Biol. 38, 193–201 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hoogenraad, C. C. & Bradke, F. Control of neuronal polarity and plasticity — a renaissance for microtubules? Trends Cell Biol. 19, 669–676 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Witte, H., Neukirchen, D. & Bradke, F. Microtubule stabilization specifies initial neuronal polarization. J. Cell Biol. 180, 619–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hammond, J. W. et al. Posttranslational modifications of tubulin and the polarized transport of kinesin-1 in neurons. Mol. Biol. Cell 21, 572–583 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jacobson, C., Schnapp, B. & Banker, G. A. A change in the selective translocation of the Kinesin-1 motor domain marks the initial specification of the axon. Neuron 49, 797–804 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Hirokawa, N. & Takemura, R. Molecular motors and mechanisms of directional transport in neurons. Nature Rev. Neurosci. 6, 201–214 (2005).

    Article  CAS  Google Scholar 

  61. Nakata, T. & Hirokawa, N. Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J. Cell Biol. 162, 1045–1055 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shea, T. B., Chan, W. K., Kushkuley, J. & Lee, S. Organizational dynamics, functions, and pathobiological dysfunctions of neurofilaments. Results Probl. Cell Differ. 48, 29–45 (2009).

    CAS  PubMed  Google Scholar 

  63. Perrot, R., Lonchampt, P., Peterson, A. C. & Eyer, J. Axonal neurofilaments control multiple fiber properties but do not influence structure or spacing of nodes of Ranvier. J. Neurosci. 27, 9573–9584 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schafer, D. P. et al. Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. J. Neurosci. 29, 13242–13254 (2009). This paper shows that one aspect of nervous system injury is loss of neuronal polarity and clustered ion channels owing to proteolysis of the AIS cytoskeleton.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Havton, L. & Kellerth, J. O. Regeneration by supernumerary axons with synaptic terminals in spinal motoneurons of cats. Nature 325, 711–714 (1987).

    Article  CAS  PubMed  Google Scholar 

  66. Fenrich, K. K. & Rose, P. K. Spinal interneuron axons spontaneously regenerate after spinal cord injury in the adult feline. J. Neurosci. 29, 12145–12158 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fenrich, K. K. et al. Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy. J. Comp. Neurol. 502, 1079–1097 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gomis-Ruth, S., Wierenga, C. J. & Bradke, F. Plasticity of polarization: changing dendrites into axons in neurons integrated in neuronal circuits. Curr. Biol. 18, 992–1000 (2008).

    Article  PubMed  CAS  Google Scholar 

  69. Inda, M. C., Defelipe, J. & Munoz, A. Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proc. Natl Acad. Sci. USA 103, 2920–2925 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ferreira, M. A. et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nature Genet. 40, 1056–1058 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Zweier, C. et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 85, 655–666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lewis, D. A., Hashimoto, T. & Volk, D. W. Cortical inhibitory neurons and schizophrenia. Nature Rev. Neurosci. 6, 312–324 (2005).

    Article  CAS  Google Scholar 

  73. Cruz, D. A., Weaver, C. L., Lovallo, E. M., Melchitzky, D. S. & Lewis, D. A. Selective alterations in postsynaptic markers of chandelier cell inputs to cortical pyramidal neurons in subjects with schizophrenia. Neuropsychopharmacology 34, 2112–2124 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Ango, F. et al. Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at purkinje axon initial segment. Cell 119, 257–272 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Burkarth, N., Kriebel, M., Kranz, E. U. & Volkmer, H. Neurofascin regulates the formation of gephyrin clusters and their subsequent translocation to the axon hillock of hippocampal neurons. Mol. Cell. Neurosci. 36, 59–70 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Ogiwara, I. et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27, 5903–5914 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gardiner, M. Genetics of idiopathic generalized epilepsies. Epilepsia 46, (Suppl. 9) 15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, Z. et al. Long-term increasing co-localization of SCN8A and ankyrin-G in rat hippocampal cornu ammonis 1 after pilocarpine induced status epilepticus. Brain Res. 1270, 112–120 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Waxman, S. G. Transcriptional channelopathies: an emerging class of disorders. Nature Rev. Neurosci. 2, 652–659 (2001).

    Article  CAS  Google Scholar 

  80. Coman, I. et al. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 129, 3186–3195 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Howell, O. W. et al. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129, 3173–3185 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Craner, M. J. et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc. Natl Acad. Sci. USA 101, 8168–8173 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mathey, E. K. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 204, 2363–2372 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Susuki, K. et al. Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers. J. Neurosci. 27, 3956–3967 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lonigro, A. & Devaux, J. J. Disruption of neurofascin and gliomedin at nodes of Ranvier precedes demyelination in experimental allergic neuritis. Brain 132, 260–273 (2009).

    Article  PubMed  Google Scholar 

  86. Kuba, H., Ishii, T. M. & Ohmori, H. Axonal site of spike initiation enhances auditory coincidence detection. Nature 444, 1069–1072 (2006). This remarkable paper shows that the position of the AIS can be regulated for optimal neuron function.

    Article  CAS  PubMed  Google Scholar 

  87. Aman, T. K. et al. Regulation of persistent Na current by interactions between β subunits of voltage-gated Na channels. J. Neurosci. 29, 2027–2042 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Szabadics, J. et al. Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits. Science 311, 233–235 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Grubb, M. S. & Burrone, J. Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature 465, 1070–1074 (2010). This paper shows that neuronal activity can cause a change in the location of the AIS towards more distal regions of the axon, thereby regulating neuronal activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kuba, H., Oichi, Y. & Ohmori, H. Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature 465, 1075–1078 (2010). This paper demonstrates that presynaptic activity can directly modulate the properties and location of the AIS, indicating the plastic nature of the spike initiation zone.

    Article  CAS  PubMed  Google Scholar 

  91. Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jeffress, L. A. A place theory of sound localization. J. Comp. Physiol. Psychol. 41, 35–39 (1948).

    Article  CAS  PubMed  Google Scholar 

  93. Seidl, A. H., Rubel, E. W. & Harris, D. M. Mechanisms for adjusting interaural time differences to achieve binaural coincidence detection. J. Neurosci. 30, 70–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Court, F. A. et al. Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves. Nature 431, 191–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Garcia, M. L. et al. NF-M is an essential target for the myelin-directed 'outside-in' signaling cascade that mediates radial axonal growth. J. Cell Biol. 163, 1011–1020 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Katsuki, T., Ailani, D., Hiramoto, M. & Hiromi, Y. Intra-axonal patterning: intrinsic compartmentalization of the axonal membrane in Drosophila neurons. Neuron 64, 188–199 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthew N. Rasband.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Matthew N. Rasband's homepage

Glossary

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.

Juxtaparanodes

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rasband, M. The axon initial segment and the maintenance of neuronal polarity. Nat Rev Neurosci 11, 552–562 (2010). https://doi.org/10.1038/nrn2852

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2852

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing