AccScience Publishing / AN / Volume 2 / Issue 1 / DOI: 10.36922/an.v2i1.274
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REVIEW

An update on axon initial segment structure and function

Zhiya Chen1,2 Takahiko Mochizuki1 Yan Zhang1*
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1 State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China
2 Yiwu Boya Rehabilitation Hospital, Yiwu City, Zhejiang Province, 322000, China
Advanced Neurology 2023, 2(1), 274 https://doi.org/10.36922/an.v2i1.274
Submitted: 24 November 2022 | Accepted: 10 January 2023 | Published: 1 February 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

The axon initial segment (AIS) is a specialized subcellular region located at the proximal end of the axon and serves as the action potential initiation site due to the high density of ion channels. The AIS plays a critical role in maintaining neuronal polarity by regulating the trafficking and distribution of proteins that function in the dendritic or axonal compartment of the neuron. Due to the adaptive nature of AIS location and length, the excitability of neurons can be altered in response to activity. In this review, we briefly introduce the structure and function of AIS as well as discuss the recent progress in our understanding of AIS ion channel distribution and plasticity in different types of neurons. These would contribute to a better understanding of the AIS and give us a new perspective on AIS-related diseases.

Keywords
Axon initial segment
Ankyrin G
Ion channels
Plasticity
Funding
National Science and Technology Innovation 2030-Major Program of “Brain Science and Brain-Like Research”
National Natural Science Foundation of China (NSFC) general research grants
Qidong-PKU SLS Innovation Fund
References
[1]

Bender KJ, Trussell LO, 2012, The physiology of the axon initial segment. Annu Rev Neurosci, 35: 249–265. https://doi.org/10.1146/annurev-neuro-062111-150339

[2]

Clark BD, Goldberg EM, Rudy B, 2009, Electrogenic tuning of the axon initial segment. Neuroscientist, 15: 651–668. https://doi.org/10.1177/1073858409341973

[3]

Grubb MS, Shu Y, Kuba H, et al., 2011, Short-and long-term plasticity at the axon initial segment. J Neurosci, 31: 16049–16055. https://doi.org/10.1523/JNEUROSCI.4064-11.2011

[4]

Hamdan H, Lim BC, Torii T, et al., 2020, Mapping axon initial segment structure and function by multiplexed proximity biotinylation. Nat Commun, 11: 100. https://doi.org/10.1038/s41467-019-13658-5

[5]

Kole MH, Stuart GJ, 2012, Signal processing in the axon initial segment. Neuron, 73: 235–247. https://doi.org/10.1016/j.neuron.2012.01.007

[6]

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

[7]

Grubb MS, Burrone J, 2010, Building and maintaining the axon initial segment. Curr Opin Neurobiol, 20: 481–488. https://doi.org/10.1016/j.conb.2010.04.012

[8]

Kordeli E, Lambert S, Bennett V, 1995, 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. https://doi.org/10.1074/jbc.270.5.2352 

[9]

Jenkins PM, Kim N, Jones SL, et al., 2015, Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling. Proc Natl Acad Sci U S A, 112: 957–964. https://doi.org/10.1073/pnas.1416544112

[10]

Leterrier C, 2016, The axon initial segment, 50 years later: A nexus for neuronal organization and function. Curr Top Membr, 77: 185–233. https://doi.org/10.1016/bs.ctm.2015.10.005

[11]

Boiko T, Vakulenko M, Ewers H, et al., 2007, 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. https://doi.org/10.1523/JNEUROSCI.4302-06.2007

[12]

Galiano MR, Jha S, Ho TS, et al., 2012, A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell, 149: 1125–1139. https://doi.org/10.1016/j.cell.2012.03.039

[13]

Davis JQ, Lambert S, Bennett V, 1996, Molecular composition of the node of Ranvier: Identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J Cell Biol, 135: 1355–1367. https://doi.org/10.1083/jcb.135.5.1355

[14]

Wang Y, Ji T, Nelson AD, et al., 2018, Critical roles of αII spectrin in brain development and epileptic encephalopathy. J Clin Invest, 128: 760–773. https://doi.org/10.1172/JCI95743

[15]

Leterrier C, Vacher H, Fache MP, et al., 2011, End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment. Proc Natl Acad Sci U S A, 108: 8826–8831. https://doi.org/10.1073/pnas.1018671108

[16]

Kuijpers M, van de Willige D, Freal A, et al., 2016, Dynein regulator NDEL1 controls polarized cargo transport at the axon initial segment. Neuron, 89, 461–471. https://doi.org/10.1016/j.neuron.2016.01.022

[17]

Bender KJ, Trussell LO, 2009, Axon initial segment Ca2+ channels influence action potential generation and timing. Neuron, 61: 259–271. https://doi.org/10.1016/j.neuron.2008.12.004

[18]

Colbert CM, Pan E, 2002, Ion channel properties underlying axonal action potential initiation in pyramidal neurons. Nat Neurosci, 5: 533–538. https://doi.org/10.1038/nn0602-857 

[19]

Fleidervish IA, Lasser-Ross N, Gutnick MJ, et al., 2010, Na+ imaging reveals little difference in action potential-evoked Na+ influx between axon and soma. Nat Neurosci, 13: 852–860. https://doi.org/10.1038/nn.2574

[20]

Lorincz A, Nusser Z, 2008, Cell-type-dependent molecular composition of the axon initial segment. J Neurosci, 28: 14329–14340. https://doi.org/10.1523/JNEUROSCI.4833-08.2008

[21]

Bean BP, 2007, The action potential in mammalian central neurons. Nat Rev Neurosci, 8: 451–465. https://doi.org/10.1038/nrn2148

[22]

Rush AM, Dib-Hajj SD, Waxman SG, 2005, Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones. J Physiol, 564: 803–815. https://doi.org/10.1113/jphysiol.2005.083089

[23]

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. https://doi.org/10.1126/science.1085167

[24]

Gasser A, Ho TS, Cheng X, et al., 2012, An ankyrinG-binding motif is necessary and sufficient for targeting Nav1.6 sodium channels to axon initial segments and nodes of Ranvier. J Neurosci, 32: 7232–7243. https://doi.org/10.1523/JNEUROSCI.5434-11.2012

[25]

Lemaillet G, Walker B, Lambert S, 2003, Identification of a conserved ankyrin-binding motif in the family of sodium channel alpha subunits. J Biol Chem, 278: 27333–27339. https://doi.org/10.1074/jbc.M303327200

[26]

Srinivasan Y, Elmer L, Davis J, et al., 1988, Ankyrin and spectrin associate with voltage-dependent sodium channels in brain. Nature, 333: 177–180. https://doi.org/10.1038/333177a0

[27]

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. Nat Neurosci, 12: 996–1002. https://doi.org/10.1038/nn.2359 

[28]

Kole MH, Ilschner SU, Kampa BM, et al., 2008, Action potential generation requires a high sodium channel density in the axon initial segment. Nat Neurosci, 11: 178–186. https://doi.org/10.1038/nn2040

[29]

Lorincz A, Nusser Z, 2010, Molecular identity of dendritic voltage-gated sodium channels. Science, 328: 906–909. https://doi.org/10.1126/science.1187958

[30]

Boiko T, Van Wart A, Caldwell JH, et al., 2003, Functional specialization of the axon initial segment by isoform-specific sodium channel targeting. J Neurosci, 23: 2306–2313. https://doi.org/10.1523/JNEUROSCI.23-06-02306.2003

[31]

Duflocq A, Le Bras B, Bullier E, et al., 2008, Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Mol Cell Neurosci, 39: 180–192. https://doi.org/10.1016/j.mcn.2008.06.008

[32]

Dumenieu M, Oule M, Kreutz MR, et al., 2017, The segregated expression of voltage-gated potassium and sodium channels in neuronal membranes: Functional implications and regulatory mechanisms. Front Cell Neurosci, 11: 115. https://doi.org/10.3389/fncel.2017.00115 

[33]

Inda MC, DeFelipe J, Munoz A, 2006, Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proc Natl Acad Sci U S A, 103: 2920–2925. https://doi.org/10.1073/pnas.0511197103

[34]

Kole MH, Letzkus JJ, Stuart GJ, 2007, Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. Neuron, 55: 633–647. https://doi.org/10.1016/j.neuron.2007.07.031

[35]

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. J Neurosci, 26: 2599–2613. https://doi.org/10.1523/JNEUROSCI.4314-05.2006

[36]

Ogawa Y, Horresh I, Trimmer JS, et al., 2008, Postsynaptic density-93 clusters Kv1 channels at axon initial segments independently of Caspr2. J Neurosci, 28: 5731–5739. https://doi.org/10.1523/JNEUROSCI.4431-07.2008

[37]

Bender KJ, Ford CP, Trussell LO, 2010, Dopaminergic modulation of axon initial segment calcium channels regulates action potential initiation. Neuron, 68: 500–511. https://doi.org/10.1016/j.neuron.2010.09.026

[38]

Thome C, Kelly T, Yanez A, et al., 2014, Axon-carrying  dendrites convey privileged synaptic input in hippocampal neurons. Neuron, 83: 1418–1430. https://doi.org/10.1016/j.neuron.2014.08.013

[39]

Triarhou LC, 2014, Axons emanating from dendrites: Phylogenetic repercussions with Cajalian hues. Front Neuroanat, 8: 133. https://doi.org/10.3389/fnana.2014.00133

[40]

Chen ZY, Peng L, Zhao M, et al., 2022, Differences in action potential propagation speed and axon initial segment plasticity between neurons from Sprague-Dawley rats and C57BL/6 mice. Zool Res, 43: 615–633. https://doi.org/10.24272/j.issn.2095-8137.2022.121

[41]

Araki T, Otani T, 1955, Response of single motoneurons to direct stimulation in toad’s spinal cord. J Neurophysiol, 18: 472–485. https://doi.org/10.1152/jn.1955.18.5.472

[42]

Coombs JS, Eccles JC, Fatt P, 1955, The electrical properties of the motoneurone membrane. J Physiol, 130: 291–325. https://doi.org/10.1113/jphysiol.1955.sp005411

[43]

Fuortes MG, Frank K, Becker MC, 1957, Steps in the production of motoneuron spikes. J Gen Physiol, 40: 735–752. https://doi.org/10.1085/jgp.40.5.735

[44]

Catterall WA, 1981, Localization of sodium channels in cultured neural cells. J Neurosci, 1: 777–783. https://doi.org/10.1523/JNEUROSCI.01-07-00777.1981

[45]

Foust A, Popovic M, Zecevic D, et al., 2010, Action potentials initiate in the axon initial segment and propagate through axon collaterals reliably in cerebellar Purkinje neurons. J Neurosci, 30: 6891–6902. https://doi.org/10.1523/JNEUROSCI.0552-10.2010

[46]

Khaliq ZM, Raman IM, 2006, Relative contributions of axonal and somatic Na channels to action potential initiation in cerebellar Purkinje neurons. J Neurosci, 26: 1935–1944. https://doi.org/10.1523/JNEUROSCI.4664-05.2006

[47]

Liao Y, Anttonen AK, Liukkonen E, et al., 2010, SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology, 75: 1454–1458. https://doi.org/10.1212/WNL.0b013e3181f8812e

[48]

Schafer DP, Jha S, Liu FD, et al., 2009, Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. J Neurosci, 29: 13242–13254. https://doi.org/10.1523/JNEUROSCI.3376-09.2009

[49]

Wimmer VC, Reid CA, Mitchell S, et al., 2010, Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus. J Clin Invest, 120: 2661–2671. https://doi.org/10.1172/JCI42219

[50]

Wimmer VC, Reid CA, So EY, et al., 2010, Axon initial segment dysfunction in epilepsy. J Physiol, 588: 1829–1840. https://doi.org/10.1113/jphysiol.2010.188417

[51]

Sobotzik JM, Sie JM, Politi C, et al., 2009, AnkyrinG is required to maintain axo-dendritic polarity in vivo. Proc Natl Acad Sci U S A, 106: 17564–17569. https://doi.org/10.1073/pnas.0909267106

[52]

Eichel K, Shen K, 2022, The function of the axon initial segment in neuronal polarity. Dev Biol, 489: 47–54. https://doi.org/10.1016/j.ydbio.2022.05.016

[53]

Song AH, Wang D, Chen G, et al., 2009, A selective filter for cytoplasmic transport at the axon initial segment. Cell, 136: 1148–1160. https://doi.org/10.1016/j.cell.2009.01.016

[54]

Sun X, Wu Y, Gu M, et al., 2014, Selective filtering defect at the axon initial segment in Alzheimer’s disease mouse models. Proc Natl Acad Sci U S A, 111: 14271–14276. https://doi.org/10.1073/pnas.1411837111

[55]

Petersen JD, Kaech S, Banker G, 2014, Selective microtubule-based transport of dendritic membrane proteins arises in concert with axon specification. J Neurosci, 34: 4135–4147. https://doi.org/10.1523/JNEUROSCI.3779-13.2014

[56]

Al-Bassam S, Xu M, Wandless TJ, et al., 2012, Differential trafficking of transport vesicles contributes to the localization of dendritic proteins. Cell Rep, 2: 89–100. https://doi.org/10.1016/j.celrep.2012.05.018

[57]

Burack MA, Silverman MA, Banker G, 2000, The role of selective transport in neuronal protein sorting. Neuron, 26: 465–472. https://doi.org/10.1016/s0896-6273(00)81178-2 

[58]

Farias GG, Guardia CM, Britt DJ, et al., 2015, Sorting of dendritic and axonal vesicles at the pre-axonal exclusion zone. Cell Rep, 13: 1221–1232. https://doi.org/10.1016/j.celrep.2015.09.074

[59]

Janssen AF, Tas RP, van Bergeijk P, et al., 2017, Myosin-V induces cargo immobilization and clustering at the axon initial segment. Front Cell Neurosci, 11: 260. https://doi.org/10.3389/fncel.2017.00260

[60]

Grubb MS, Burrone J, 2010, Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature, 465: 1070–1074. https://doi.org/10.1038/nature09160 

[61]

Kuba H, Oichi Y, Ohmori H, 2010, Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature, 465: 1075–1078. https://doi.org/10.1038/nature09087

[62]

Fried SI, Lasker AC, Desai NJ, et al., 2009, Axonal sodium-channel bands shape the response to electric stimulation in retinal ganglion cells. J Neurophysiol, 101: 1972–1987. https://doi.org/10.1152/jn.91081.2008

[63]

Gutzmann A, Ergül N, Grossmann R, et al., 2014, A period of structural plasticity at the axon initial segment in developing visual cortex. Front Neuroanat, 8: 11. https://doi.org/10.3389/fnana.2014.00011

[64]

Goethals S, Brette R, 2020, Theoretical relation between axon initial segment geometry and excitability. Elife, 9: e53432. https://doi.org/10.7554/eLife.53432

[65]

Hefting LL, D’Este E, Arvedsen E, et al., 2020, Multiple domains in the Kv7.3 C-terminus can regulate localization to the axon initial segment. Front Cell Neurosci, 14: 10. https://doi.org/10.3389/fncel.2020.00010

[66]

Jamann N, Jordan M, Engelhardt M, 2018, Activity-dependent axonal plasticity in sensory systems. Neuroscience, 368: 268–282. https://doi.org/10.1016/j.neuroscience.2017.07.035 

[67]

Hinman JD, Rasband MN, Carmichael ST, 2013, Remodeling of the axon initial segment after focal cortical and white matter stroke. Stroke, 44: 182–189. https://doi.org/10.1161/STROKEAHA.112.668749

[68]

Bayer TA, Wirths O, Majtényi K, et al., 2001, Key factors in Alzheimer’s disease: Beta-amyloid precursor protein processing, metabolism and intraneuronal transport. Brain Pathol, 11: 1–11. https://doi.org/10.1111/j.1750-3639.2001.tb00376.x

[69]

Leussis MP, Madison JM, Petryshen TL, 2012, Ankyrin 3: Genetic association with bipolar disorder and relevance to disease pathophysiology. Biol Mood Anxiety Disord, 2: 18. https://doi.org/10.1186/2045-5380-2-18

[70]

Iqbal Z, Vandeweyer G, van der Voet M, et al., 2013, Homozygous and heterozygous disruptions of ANK3: At the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet, 22: 1960–1970. https://doi.org/10.1093/hmg/ddt043

[71]

Codina-Sola M, Rodríguez-Santiago B, Homs A, et al., 2015, Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Mol Autism, 6: 21. https://doi.org/10.1186/s13229-015-0017-0

[72]

Schizophrenia Psychiatric Genome-Wide Association (GWAS) Consortium, 2011, Genome-wide association study identifies five new schizophrenia loci. Nat Genet, 43: 969–976. https://doi.org/10.1038/ng.940

[73]

Parkinson NJ, Olsson CL, Hallows JL, et al., 2001, Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice. Nat Genet, 29: 61–65. https://doi.org/10.1038/ng710

[74]

Devaux JJ, 2010, The C-terminal domain of ssIV-spectrin is crucial for KCNQ2 aggregation and excitability at nodes of Ranvier. J Physiol, 588: 4719–4730. https://doi.org/10.1113/jphysiol.2010.196022

[75]

Knierim E, Gill E, Seifert F, et al., 2017, A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness. Hum Genet, 136: 903–910. https://doi.org/10.1007/s00439-017-1814-7

Conflict of interest
The authors declare no potential conflicts of interest.
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Advanced Neurology, Electronic ISSN: 2810-9619 Published by AccScience Publishing