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Presynaptic activity regulates Na+ channel distribution at the axon initial segment


Deprivation of afferent inputs in neural circuits leads to diverse plastic changes in both pre- and postsynaptic elements that restore neural activity1. The axon initial segment (AIS) is the site at which neural signals arise2,3, and should be the most efficient site to regulate neural activity. However, none of the plasticity currently known involves the AIS. We report here that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated Na+ channels and the AIS anchoring protein, increased by 1.7 times in seven days after auditory input deprivation. This was accompanied by an increase in the whole-cell Na+ current, membrane excitability and spontaneous firing. Our work demonstrates homeostatic regulation of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation.

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Figure 1: Auditory deprivation increased the length of the AIS.
Figure 2: Elongation of the AIS is activity dependent and develops within several days.
Figure 3: Auditory deprivation increased axonal I Na and excitability of neurons.
Figure 4: Auditory deprivation has little effect on synaptic transmission.


  1. Turrigiano, G. G. & Nelson, S. B. Homeostatic plasticity in the developing nervous system. Nature Rev. Neurosci. 5, 97–107 (2004)

    CAS  Article  Google Scholar 

  2. Khaliq, Z. M. & Raman, I. M. Relative contributions of axonal and somatic Na channels to action potential initiation in cerebellar Purkinje neurons. J. Neurosci. 26, 1935–1944 (2006)

    CAS  Article  Google Scholar 

  3. Palmer, L. M. & Stuart, G. J. Site of action potential initiation in layer 5 pyramidal neurons. J. Neurosci. 26, 1854–1863 (2006)

    CAS  Article  Google Scholar 

  4. Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996)

    CAS  Article  ADS  Google Scholar 

  5. Nelson, S. B. & Turrigiano, G. G. Strength through diversity. Neuron 60, 477–482 (2008)

    CAS  Article  Google Scholar 

  6. Desai, N. S., Rutherford, L. C. & Turrigiano, G. G. Plasticity in the intrinsic excitability of cortical pyramidal neurons. Nature Neurosci. 2, 515–520 (1999)

    CAS  Article  Google Scholar 

  7. Xu, J., Kang, N., Jiang, L., Nedergaard, M. & Kang, J. Activity-dependent long term potentiation of intrinsic excitability in hippocampal CA1 pyramidal neurons. J. Neurosci. 25, 1750–1760 (2005)

    CAS  Article  Google Scholar 

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

    CAS  Article  ADS  Google Scholar 

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

    CAS  Article  Google Scholar 

  10. Shu, Y., Yu, Y., Yang, J. & McCormick, D. A. Selective control of cortical axonal spikes by a slowly inactivating K+ current. Proc. Natl Acad. Sci. USA 104, 11453–11458 (2007)

    CAS  Article  ADS  Google Scholar 

  11. Bender, K. J. & Trussell, L. O. Axon initial segment Ca2+ channels influence action potential generation and timing. Neuron 61, 259–271 (2009)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  13. Kuba, H., Ishii, T. M. & Ohmori, H. Axonal site of spike initiation enhances auditory coincidence detection. Nature 444, 1069–1072 (2006)

    CAS  Article  ADS  Google Scholar 

  14. Kuba, H. & Ohmori, H. Roles of axonal sodium channels in precise auditory time coding at nucleus magnocellularis of the chick. J. Physiol. (Lond.) 587, 87–100 (2009)

    CAS  Article  Google Scholar 

  15. Born, D. E. & Rubel, E. W. Afferent influences on brain stem auditory nuclei of the chicken: neuron number and size following cochlea removal. J. Comp. Neurol. 231, 435–445 (1985)

    CAS  Article  Google Scholar 

  16. Rubel, E. W. & Fritzsch, B. Auditory system development: primary auditory neurons and their targets. Annu. Rev. Neurosci. 25, 51–101 (2002)

    CAS  Article  Google Scholar 

  17. Zeng, C., Nannapaneni, N., Zhou, J., Hughes, L. F. & Shore, S. Cochlear damage changes the distribution of vesicular glutamate transporters associated with auditory and nonauditory inputs to the cochlear nucleus. J. Neurosci. 29, 4210–4217 (2009)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  19. Tucci, D. L. & Rubel, E. W. Afferent influences on brain stem auditory nuclei of the chicken: effects of conductive and sensorineural hearing loss on n. magnocellularis. J. Comp. Neurol. 238, 371–381 (1985)

    CAS  Article  Google Scholar 

  20. Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138–145 (2000)

    CAS  Article  Google Scholar 

  21. Kubke, M. F. & Carr, C. E. Development of the auditory brainstem of birds: comparison between barn owls and chickens. Hear. Res. 147, 1–20 (1998)

    Article  Google Scholar 

  22. Jhaveri, S. & Morest, D. K. Neuronal architecture in nucleus magnocellularis of the chicken auditory system with observations on nucleus laminaris: a light and electron microscope study. Neuroscience 7, 809–836 (1982)

    CAS  Article  Google Scholar 

  23. Lu, Y., Monsivais, P., Tempel, B. L. & Rubel, E. W. Activity-dependent regulation of the potassium channel subunits Kv1.1 and Kv3.1. J. Comp. Neurol. 470, 93–106 (2004)

    CAS  Article  Google Scholar 

  24. Cerminara, N. L. & Rawson, J. A. Evidence that climbing fibers control an intrinsic spike generator in cerebellar Purkinje cells. J. Neurosci. 24, 4510–4517 (2004)

    CAS  Article  Google Scholar 

  25. Born, D. E., Durham, D. & Rubel, E. W. Afferent influences on brainstem auditory nuclei of the chick: nucleus magnocellularis neuronal activity following cochlea removal. Brain Res. 557, 37–47 (1991)

    CAS  Article  Google Scholar 

  26. Daniels, R. W. et al. A single vesicular glutamate transporter is sufficient to fill a synaptic vesicle. Neuron 49, 11–16 (2006)

    CAS  Article  Google Scholar 

  27. Lu, Y., Harris, J. A. & Rubel, E. W. Development of spontaneous miniature EPSCs in mouse AVCN neurons during a critical period of afferent-dependent neuron survival. J. Neurophysiol. 97, 635–646 (2007)

    Article  Google Scholar 

  28. Sherman, S. J. & Catterall, W. A. Electrical activity and cytosolic calcium regulate levels of tetrodotoxin-sensitive sodium channels in cultured rat muscle cells. Proc. Natl Acad. Sci. USA 81, 262–266 (1984)

    CAS  Article  ADS  Google Scholar 

  29. Rubel, E. W. & Parks, T. N. Organization and development of brain stem auditory nuclei of the chicken: tonotopic organization of N. magnocellularis and N. laminaris. J. Comp. Neurol. 164, 411–433 (1975)

    CAS  Article  Google Scholar 

  30. Bouzidi, M. et al. Interaction of the Nav1.2a subunit of the voltage-dependent sodium channel with nodal ankyrinG. In vitro mapping of the interacting domains and association in synaptosomes. J. Biol. Chem. 277, 28996–29004 (2002)

    CAS  Article  Google Scholar 

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We thank G. Alcaraz for providing ankyrin-G antibody. We also thank L. O. Trussell for advice and for editing the manuscript; M. N. Rasband, T. M. Ishii and R. Yamada for reading the manuscript; and K. Bender for discussions. This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan, to H.K. and H.O.

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H.K. designed and carried out all experiments and wrote the paper. Y.O. carried out preliminary experiments. H.O. helped with acoustic stimulation.

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Correspondence to Hiroshi Kuba.

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The authors declare no competing financial interests.

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

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