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The origin of spontaneous activity in the developing auditory system

Abstract

Spontaneous activity in the developing auditory system is required for neuronal survival as well as the refinement and maintenance of tonotopic maps in the brain. However, the mechanisms responsible for initiating auditory nerve firing in the absence of sound have not been determined. Here we show that supporting cells in the developing rat cochlea spontaneously release ATP, which causes nearby inner hair cells to depolarize and release glutamate, triggering discrete bursts of action potentials in primary auditory neurons. This endogenous, ATP-mediated signalling synchronizes the output of neighbouring inner hair cells, which may help refine tonotopic maps in the brain. Spontaneous ATP-dependent signalling rapidly subsides after the onset of hearing, thereby preventing this experience-independent activity from interfering with accurate encoding of sound. These data indicate that supporting cells in the organ of Corti initiate electrical activity in auditory nerves before hearing, pointing to an essential role for peripheral, non-sensory cells in the development of central auditory pathways.

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Figure 1: Spontaneous purinergic signalling in the developing cochlea.
Figure 2: ATP release elicits optical changes and intercellular Ca 2+ waves in Kölliker’s organ.
Figure 3: Supporting-cell-derived ATP depolarizes IHCs.
Figure 4: Supporting-cell-derived ATP triggers bursts of action potentials in auditory nerve fibres.
Figure 5: Intrinsic purinergic signalling ceases after the onset of hearing.
Figure 6: Local release of ATP synchronizes the activity of neighbouring IHCs.

References

  1. Geal-Dor, M., Freeman, S., Li, G. & Sohmer, H. Development of hearing in neonatal rats: air and bone conducted ABR thresholds. Hear. Res. 69, 236–242 (1993)

    Article  CAS  Google Scholar 

  2. Puel, J. L. & Uziel, A. Correlative development of cochlear action potential sensitivity, latency, and frequency selectivity. Brain Res. 465, 179–188 (1987)

    Article  CAS  Google Scholar 

  3. Glowatzki, E. & Fuchs, P. A. Transmitter release at the hair cell ribbon synapse. Nature Neurosci. 5, 147–154 (2002)

    Article  CAS  Google Scholar 

  4. Gummer, A. W. & Mark, R. F. Patterned neural activity in brain stem auditory areas of a prehearing mammal, the tammar wallaby (Macropus eugenii). Neuroreport 5, 685–688 (1994)

    Article  CAS  Google Scholar 

  5. Jones, T. A., Jones, S. M. & Paggett, K. C. Primordial rhythmic bursting in embryonic cochlear ganglion cells. J. Neurosci. 21, 8129–8135 (2001)

    Article  CAS  Google Scholar 

  6. Jones, T. A., Leake, P. A., Snyder, R. L., Stakhovskaya, O. & Bonham, B. H. Spontaneous discharge patterns in cochlear spiral ganglion cells prior to the onset of hearing in cats. J. Neurophysiol. doi: 10.1152/jn.00472.2007 (8 August 2007)

  7. Walsh, E. J. & McGee, J. Postnatal development of auditory nerve and cochlear nucleus neuronal responses in kittens. Hear. Res. 28, 97–116 (1987)

    Article  CAS  Google Scholar 

  8. Lippe, W. R. Rhythmic spontaneous activity in the developing avian auditory system. J. Neurosci. 14, 1486–1495 (1994)

    Article  CAS  Google Scholar 

  9. Retzius, G. Das Gehörorgan der Wirbelthiere. II. Das Gehörorgan der Reptilien, der Vögel und Säugethiere (Samson & Wallin, Stockholm, 1884)

    Google Scholar 

  10. Hinojosa, R. A note on development of Corti’s organ. Acta Otolaryngol. (Stockh.) 84, 238–251 (1977)

    Article  CAS  Google Scholar 

  11. Wada, T. Anatomical and physiological studies on the growth of the inner ear of the albino rat. Am. Anat. Mem. 10, 1–174 (1923)

    Google Scholar 

  12. Eybalin, M. Neurotransmitters and neuromodulators of the mammalian cochlea. Physiol. Rev. 73, 309–373 (1993)

    Article  CAS  Google Scholar 

  13. Glowatzki, E. & Fuchs, P. A. Cholinergic synaptic inhibition of inner hair cells in the neonatal mammalian cochlea. Science 288, 2366–2368 (2000)

    Article  CAS  ADS  Google Scholar 

  14. Fuchs, P. A., Evans, M. G. & Murrow, B. W. Calcium currents in hair cells isolated from the cochlea of the chick. J. Physiol. (Lond.) 429, 553–568 (1990)

    Article  CAS  Google Scholar 

  15. Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 87, 659–797 (2007)

    Article  CAS  Google Scholar 

  16. Housley, G. D. Physiological effects of extracellular nucleotides in the inner ear. Clin. Exp. Pharmacol. Physiol. 27, 575–580 (2000)

    Article  CAS  Google Scholar 

  17. North, R. A. Molecular physiology of P2X receptors. Physiol. Rev. 82, 1013–1067 (2002)

    Article  CAS  Google Scholar 

  18. Bennett, M. V., Contreras, J. E., Bukauskas, F. F. & Saez, J. C. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 26, 610–617 (2003)

    Article  CAS  Google Scholar 

  19. Forge, A. et al. Gap junctions in the inner ear: comparison of distribution patterns in different vertebrates and assessment of connexin composition in mammals. J. Comp. Neurol. 467, 207–231 (2003)

    Article  Google Scholar 

  20. Zhao, H. B. Connexin26 is responsible for anionic molecule permeability in the cochlea for intercellular signalling and metabolic communications. Eur. J. Neurosci. 21, 1859–1868 (2005)

    Article  Google Scholar 

  21. Charles, A. & Giaume, C. Intercellular Calcium Waves in Astrocytes: Underlying Mechanisms and Functional Significance (eds Volterra, A., Magistretti, P. J. & Haydon, P. G.) (Oxford Univ. Press, Oxford, 2002)

    Google Scholar 

  22. Piazza, V., Ciubotaru, C. D., Gale, J. E. & Mammano, F. Purinergic signalling and intercellular Ca2+ wave propagation in the organ of Corti. Cell Calcium 41, 77–86 (2007)

    Article  CAS  Google Scholar 

  23. Salih, S. G., Jagger, D. J. & Housley, G. D. ATP-gated currents in rat primary auditory neurones in situ arise from a heteromultimetric P2X receptor subunit assembly. Neuropharmacology 42, 386–395 (2002)

    Article  CAS  Google Scholar 

  24. Sugasawa, M., Erostegui, C., Blanchet, C. & Dulon, D. ATP activates non-selective cation channels and calcium release in inner hair cells of the guinea-pig cochlea. J. Physiol. (Lond.) 491, 707–718 (1996)

    Article  CAS  Google Scholar 

  25. Jones, T. A. & Jones, S. M. Spontaneous activity in the statoacoustic ganglion of the chicken embryo. J. Neurophysiol. 83, 1452–1468 (2000)

    Article  CAS  Google Scholar 

  26. Rübsamen, R. & Lippe, W. R. in Development of the Auditory System (eds Rubel, E. W., Popper, A. N. & Fay, R. R.) 193–270 (Springer, New York, 1998)

    Book  Google Scholar 

  27. Müller, M. Frequency representation in the rat cochlea. Hear. Res. 51, 247–254 (1991)

    Article  Google Scholar 

  28. Beutner, D. & Moser, T. The presynaptic function of mouse cochlear inner hair cells during development of hearing. J. Neurosci. 21, 4593–4599 (2001)

    Article  CAS  Google Scholar 

  29. Marcotti, W., Johnson, S. L., Rüsch, A. & Kros, C. J. Sodium and calcium currents shape action potentials in immature mouse inner hair cells. J. Physiol. (Lond.) 552, 743–761 (2003)

    Article  CAS  Google Scholar 

  30. Friauf, E. & Lohmann, C. Development of auditory brainstem circuitry. Activity-dependent and activity-independent processes. Cell Tissue Res. 297, 187–195 (1999)

    Article  CAS  Google Scholar 

  31. Kandler, K. Activity-dependent organization of inhibitory circuits: lessons from the auditory system. Curr. Opin. Neurobiol. 14, 96–104 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Leao, R. N. et al. Topographic organization in the auditory brainstem of juvenile mice is disrupted in congenital deafness. J. Physiol. (Lond.) 571, 563–578 (2006)

    Article  CAS  Google Scholar 

  34. Leake, P. A., Hradek, G. T., Chair, L. & Snyder, R. L. Neonatal deafness results in degraded topographic specificity of auditory nerve projections to the cochlear nucleus in cats. J. Comp. Neurol. 497, 13–31 (2006)

    Article  Google Scholar 

  35. Gabriele, M. L., Brunso-Bechtold, J. K. & Henkel, C. K. Plasticity in the development of afferent patterns in the inferior colliculus of the rat after unilateral cochlear ablation. J. Neurosci. 20, 6939–6949 (2000)

    Article  CAS  Google Scholar 

  36. Kros, C. J., Rüppersberg, J. P. & Rüsch, A. Expression of a potassium current in inner hair cells during development of hearing in mice. Nature 394, 281–284 (1998)

    Article  CAS  ADS  Google Scholar 

  37. Marcotti, W., Johnson, S. L., Holley, M. C. & Kros, C. J. Developmental changes in the expression of potassium currents of embryonic, neonatal and mature mouse inner hair cells. J. Physiol. (Lond.) 548, 383–400 (2003)

    Article  CAS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  39. Kotak, V. C. & Sanes, D. H. Synaptically evoked prolonged depolarizations in the developing auditory system. J. Neurophysiol. 74, 1611–1620 (1995)

    Article  CAS  Google Scholar 

  40. Huberman, A. D. Mechanisms of eye-specific visual circuit development. Curr. Opin. Neurobiol. 17, 73–80 (2007)

    Article  CAS  Google Scholar 

  41. Erazo-Fischer, E., Striessnig, J. & Taschenberger, H. The role of physiological afferent nerve activity during in vivo maturation of the calyx of Held synapse. J. Neurosci. 27, 1725–1737 (2007)

    Article  CAS  Google Scholar 

  42. Lagostena, L. & Mammano, F. Intracellular calcium dynamics and membrane conductance changes evoked by Deiters’ cell purinoceptor activation in the organ of Corti. Cell Calcium 29, 191–198 (2001)

    Article  CAS  Google Scholar 

  43. Gale, J. E., Piazza, V., Ciubotaru, C. D. & Mammano, F. A mechanism for sensing noise damage in the inner ear. Curr. Biol. 14, 526–529 (2004)

    Article  CAS  Google Scholar 

  44. Fields, R. D. & Burnstock, G. Purinergic signalling in neuron–glia interactions. Nature Rev. Neurosci. 7, 423–436 (2006)

    Article  CAS  Google Scholar 

  45. Nedergaard, M., Ransom, B. & Goldman, S. A. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 26, 523–530 (2003)

    Article  CAS  Google Scholar 

  46. Glowatzki, E. et al. The glutamate-aspartate transporter GLAST mediates glutamate uptake at inner hair cell afferent synapses in the mammalian cochlea. J. Neurosci. 26, 7659–7664 (2006)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J.-H. Kong for help with preliminary experiments, and P. Fuchs, J. Howell and M. Lahne for discussions. This work was supported by a Royal Society University Research Fellowship (to J.E.G.), National Institutes of Health Grants (to E.G. and D.E.B.) and the Deafness Research Foundation (to D.E.B.).

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Correspondence to Dwight E. Bergles.

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Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-6 with Legends and Supplementary Video Legends. Supplementary Figures 1-6 and their legends provide evidence for correlation between spontaneous field potentials and inward currents in supporting cells, additional pharmacology of spontaneous extracellular potentials and spontaneous inward currents in supporting cells and inner hair cells, and further characterization of spontaneous optical changes and ATP-elicited Ca2+ transients within the developing cochlea. (PDF 12570 kb)

Supplementary Video 1a

The file contains Supplementary Video 1a showing time lapse of the unprocessed transmitted light (IR-DIC) signal acquired from a P8 rat organ of Corti illustrates the intrinsic optical changes that spontaneously occur in the supporting cells of Kölliker’s organ. (MOV 6687 kb)

Supplementary Video 1b

The file contains Supplementary Video 1b showing time lapse of Supplementary Video 1 after image subtraction, providing an index of transmitted light change over time. (MOV 10102 kb)

Supplementary Video 1c

The file contains Supplementary Video 1c showing time lapse of Supplementary Video 1 after image subtraction, thresholding and pseudocoloring. (MOV 2499 kb)

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Tritsch, N., Yi, E., Gale, J. et al. The origin of spontaneous activity in the developing auditory system. Nature 450, 50–55 (2007). https://doi.org/10.1038/nature06233

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