Axon Initial Segment


The axon initial segment (AIS) is a specialised region of the axon where the action potential is initiated following integration of excitatory and inhibitory inputs. The AIS contains high density of sodium and potassium channels anchored on scaffold proteins, but it also includes receptors to neurotransmitters and neuromodulators. Besides its role in action potential initiation, the AIS constitutes a diffusion barrier that controls cytoplasmic traffic towards the axon. Activity‐dependent plasticity has been recently shown to affect the length and position of the AIS whereas stimulation of ligand‐gated receptors alters the ion channel content of the AIS. Thus, the AIS represents a critical element in neuronal excitability and its plasticity.

Key Concepts

  • The axon initial segment is the site of action potential initiation.
  • It is enriched with high density of voltage‐gated sodium and potassium channels.
  • Ion channels are anchored at the AIS through scaffold proteins.
  • The AIS constitutes a barrier for molecular and cellular traffic from the soma to the axon and is, therefore, essential to maintain axonal identity.
  • The structure and function of the AIS is subject to activity‐dependent plasticity.

Keywords: action potential; ion channels; neuron; excitability; plasticity

Figure 1. Structure and composition of the AIS. Inputs originated from the dendrites are integrated at the AIS where the AP is triggered. The propagation of the spikes to the presynaptic terminal is made possible by nodes of Ranvier, which composition is similar to AIS. The membrane of AIS is characterised by a high concentration of sodium channels (Nav), 50 times higher than in soma. Other potassium and calcium voltage‐gated ion channels (Kv and Cav) contribute to modulate excitability. These channels are anchored and concentrated through scaffold proteins like AnkyrinG and PSD‐93. AnkyrinG is anchored to the AIS actin microfilaments by βIV‐spectrin. Both actin microfilaments and microtubules have distinctive characteristics at the AIS and its contribution to AIS structure and function is still mostly unknown. All this complex structure is modulated through recently identified kinases (such as CK2 or GSK3) and phosphatases (such as calcineurin).
Figure 2. Function of the AIS. (a) Spike initiation in the AIS. Dual AIS‐soma recording from a pyramidal neuron. Left, recording configuration. Right, action potential measured in the soma is slightly delayed compared to that measured in the AIS. (b) Spike threshold at the AIS and the cell body. Simultaneous recording from L5 pyramidal neuron in the AIS (left) and the soma (right). While the rheobase is lower in the AIS compared to the soma, the voltage threshold is higher. Reproduced with permission from Kole and Stuart . © Springer Nature.
Figure 3. Plasticity of the AIS. (a) Elongation of the AIS. Following activity deprivation, the length of the AIS is increased. Reproduced with permission from Kuba et al. . © Springer Nature. (b) Shift in the AIS position. Following activity enhancement, the AIS position is shifted away from the soma. Reproduced with permission from Grubb and Burrone . © Springer Nature. (c) Change in composition of the AIS. Following stimulation of P2X7 receptor, the density of ankyrin G is reduced. Reproduced with permission from Del Puerto et al. . © Oxford University Press.


Azouz R and Gray CM (2000) Dynamic spike threshold reveals a mechanism for synaptic coincidence detection in cortical neurons in vivo. Proceedings of the National Academy of Sciences of the United States of America 97: 8110–8115.

Bas Orth C, Schultz C, Muller CM, Frotscher M and Deller T (2007) Loss of the cisternal organelle in the axon initial segment of cortical neurons in synaptopodin‐deficient mice. Journal of Comparative Neurology 504: 441–449.

Bean BP (2007) The action potential in mammalian central neurons. Nature Review Neuroscience 8: 451–465.

Bender KJ, Ford CP and Trussell LO (2010) Dopaminergic modulation of axon initial segment calcium channels regulates action potential initiation. Neuron 68: 500–511.

Bender KJ and Trussell LO (2012) The physiology of the axon initial segment. Annual Review of Neuroscience 35: 249–265.

Benedeczky I, Molnar E and Somogyi P (1994) The cisternal organelle as a Ca(2+)‐storing compartment associated with GABAergic synapses in the axon initial segment of hippocampal pyramidal neurones. Experimental Brain Research 101: 216–230.

Berger SL, Leo‐Macias A, Yuen S, et al. (2018) Localized myosin II activity regulates assembly and plasticity of the axon initial segment. Neuron 97 (555–570): e556.

Brechet A, Fache MP, Brachet A, et al. (2008) Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interactions with ankyrin G. Journal of Cell Biology 183: 1101–1114.

Brette R (2013) Sharpness of spike initiation in neurons explained by compartmentalization. PLoS Computational Biology 9: e1003338.

Christie SB and De Blas AL (2003) GABAergic and glutamatergic axons innervate the axon initial segment and organize GABA(A) receptor clusters of cultured hippocampal pyramidal cells. Journal of Comparative Neurology 456: 361–374.

Cudmore RH, Fronzaroli‐Molinieres L, Giraud P and Debanne D (2010) Spike‐time precision and network synchrony are controlled by the homeostatic regulation of the D‐type potassium current. Journal of Neuroscience 30: 12885–12895.

Del Puerto A, Fronzaroli‐Molinieres L, Perez‐Alvarez MJ, et al. (2015) ATP‐P2X7 receptor modulates axon initial segment composition and function in physiological conditions and brain injury. Cerebral Cortex 25: 2282–2294.

Evans MD, Sammons RP, Lebron S, et al. (2013) Calcineurin signaling mediates activity‐dependent relocation of the axon initial segment. Journal of Neuroscience 33: 6950–6963.

Garrido JJ, Giraud P, Carlier E, et al. (2003) A targeting motif involved in sodium channel clustering at the axonal initial segment. Science 300: 2091–2094.

Grubb MS and Burrone J (2010) Activity‐dependent relocation of the axon initial segment fine‐tunes neuronal excitability. Nature 465: 1070–1074.

Hedstrom KL, Ogawa Y and Rasband MN (2008) AnkyrinG is required for maintenance of the axon initial segment and neuronal polarity. Journal of Cell Biology 183: 635–640.

Higgs MH and Spain WJ (2011) Kv1 channels control spike threshold dynamics and spike timing in cortical pyramidal neurones. Journal of Physiology 589: 5125–5142.

Hu W, Tian C, Li T, et al. (2009) Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation. Nature Neuroscience 12: 996–1002.

Janssen AFJ, Tas RP, van Bergeijk P, et al. (2017) Myosin‐V induces cargo immobilization and clustering at the axon initial segment. Frontiers in Cellular Neuroscience 11: 260.

Jenkins SM and Bennett V (2001) Ankyrin‐G coordinates assembly of the spectrin‐based membrane skeleton, voltage‐gated sodium channels, and L1 CAMs at Purkinje neuron initial segments. Journal of Cell Biology 155: 739–746.

Jensen CS, Watanabe S, Stas JI, et al. (2017) Trafficking of Kv2.1 channels to the axon initial segment by a novel nonconventional secretory pathway. Journal of Neuroscience 37: 11523–11536.

Ko KW, Rasband MN, Meseguer V, Kramer RH and Golding NL (2016) Serotonin modulates spike probability in the axon initial segment through HCN channels. Nature Neuroscience 19: 826–834.

Kobayashi T, Storrie B, Simons K and Dotti CG (1992) A functional barrier to movement of lipids in polarized neurons. Nature 359: 647–650.

Kole MH, Ilschner SU, Kampa BM, et al. (2008) Action potential generation requires a high sodium channel density in the axon initial segment. Nature Neuroscience 11: 178–186.

Kole MH and Stuart GJ (2008) Is action potential threshold lowest in the axon? Nature Neuroscience 11: 1253–1255.

Kuba H, Oichi Y and Ohmori H (2010) Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature 465: 1075–1078.

Kuba H, Yamada R, Ishiguro G and Adachi R (2015) Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity. Nature Communications 6: 8815.

Lezmy J, Lipinsky M, Khrapunsky Y, et al. (2017) M‐current inhibition rapidly induces a unique CK2‐dependent plasticity of the axon initial segment. Proceedings of the National Academy of Sciences of the United States of America 114: E10234–E10243.

Nusser Z, Roberts JD, Baude A, et al. (1995) Immunocytochemical localization of the alpha 1 and beta 2/3 subunits of the GABAA receptor in relation to specific GABAergic synapses in the dentate gyrus. European Journal of Neuroscience 7: 630–646.

Ogawa Y, Horresh I, Trimmer JS, et al. (2008) Postsynaptic density‐93 clusters Kv1 channels at axon initial segments independently of Caspr2. Journal of Neuroscience 28: 5731–5739.

Palay SL, Sotelo C, Peters A and Orkand PM (1968) The axon hillock and the initial segment. Journal of Cell Biology 38: 193–201.

Palmer LM and Stuart GJ (2006) Site of action potential initiation in layer 5 pyramidal neurons. Journal of Neuroscience 26: 1854–1863.

Pan Z, Kao T, Horvath Z, et al. (2006) A common ankyrin‐G‐based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. Journal of Neuroscience 26: 2599–2613.

Popovic MA, Foust AJ, McCormick DA and Zecevic D (2011) The spatio‐temporal characteristics of action potential initiation in layer 5 pyramidal neurons: a voltage imaging study. Journal of Physiology 589: 4167–4187.

Rasband MN (2010) The axon initial segment and the maintenance of neuronal polarity. Nature Review Neuroscience 11: 552–562.

Sanchez‐Ponce D, DeFelipe J, Garrido JJ and Munoz A (2012) Developmental expression of Kv potassium channels at the axon initial segment of cultured hippocampal neurons. PLoS One 7.

Sanchez‐Ponce D, Munoz A and Garrido JJ (2011) Casein kinase 2 and microtubules control axon initial segment formation. Molecular and Cellular Neuroscience 46: 222–234.

Schafer DP, Jha S, Liu F, et al. (2009) Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. Journal of Neuroscience 29: 13242–13254.

Schluter A, Del Turco D, Deller T, et al. (2017) Structural plasticity of synaptopodin in the axon initial segment during visual cortex development. Cerebral Cortex 27: 4662–4675.

Shea TB (1999) Selective stabilization of microtubules within the proximal region of developing axonal neurites. Brain Research Bulletin 48: 255–261.

Song AH, Wang D, Chen G, et al. (2009) A selective filter for cytoplasmic transport at the axon initial segment. Cell 136: 1148–1160.

Tapia M, Wandosell F and Garrido JJ (2010) Impaired function of HDAC6 slows down axonal growth and interferes with axon initial segment development. PLoS One 5: e12908.

Tapia M, Del Puerto A, Puime A, et al. (2013) GSK3 and beta‐catenin determines functional expression of sodium channels at the axon initial segment. Cellular and Molecular Life Sciences 70: 105–120.

Tapia M, Dominguez A, Zhang W, et al. (2017) Cannabinoid receptors modulate neuronal morphology and AnkyrinG density at the axon initial segment. Frontiers in Cellular Neuroscience 11: 5.

Vacher H, Mohapatra DP and Trimmer JS (2008) Localization and targeting of voltage‐dependent ion channels in mammalian central neurons. Physiological Reviews 88: 1407–1447.

van Beuningen SFB, Will L, Harterink M, et al. (2015) TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays. Neuron 88: 1208–1226.

Wester JC and Contreras D (2013) Biophysical mechanism of spike threshold dependence on the rate of rise of the membrane potential by sodium channel inactivation or subthreshold axonal potassium current. Journal of Computational Neuroscience 35: 1–17.

Winckler B, Forscher P and Mellman I (1999) A diffusion barrier maintains distribution of membrane proteins in polarized neurons. Nature 397: 698–701.

Xu K, Zhong G and Zhuang X (2013) Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science 339: 452–456.

Yoshimura T, Stevens SR, Leterrier C, Stankewich MC and Rasband MN (2016) Developmental changes in expression of betaIV spectrin splice variants at axon initial segments and nodes of ranvier. Frontiers in Cellular Neuroscience 10: 304.

Yu Y, Shu Y and McCormick DA (2008) Cortical action potential backpropagation explains spike threshold variability and rapid‐onset kinetics. Journal of Neuroscience 28: 7260–7272.

Zhang X, Davis JQ, Carpenter S and Bennett V (1998) Structural requirements for association of neurofascin with ankyrin. Journal of Biological Chemistry 273: 30785–30794.

Further Reading

Debanne D, Campanac E, Bialowas A, Carlier E and Alacaraz G (2011) Axon physiology. Physiological Reviews 91: 555–602.

Huang CY and Rasband M (2018) Axon initial segments: structure, function, and disease. Annals of the New York Academy of Sciences 1420: 46–61.

Jamann N, Jordan M and Engelhardt M (2018) Activity‐dependent axonal plasticity in sensory systems. Neuroscience 368: 268–282.

Kole MH and Stuart G (2012) Signal processing in the axon initial segment. Neuron 73: 235–247.

Kuba H (2012) Structural tuning and plasticity of the axon initial segment in auditory neurons. Journal of Physiology 590: 5571–5579.

Leterrier C (2018) The axon initial segment: an updated viewpoint. Journal of Neuroscience 38: 2135–2145.

Rama S, Zbili M and Debanne D (2018) Signal propagation along the axon. Current Opinion in Neurobiology 51: 37–44.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Debanne, Dominique, and Garrido, Juan José(Dec 2018) Axon Initial Segment. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000004]