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Traveling waves in developing cerebellar cortex mediated by asymmetrical Purkinje cell connectivity

Nature Neuroscience volume 12, pages 463–473 (2009)Cite this article

Abstract

Correlated network activity is important in the development of many neural circuits. Purkinje cells are among the first neurons to populate the cerebellar cortex, where they sprout exuberant axon collaterals. We used multiple patch-clamp recordings targeted with two-photon microscopy to characterize monosynaptic connections between the Purkinje cells of juvenile mice. We found that Purkinje cell axon collaterals projected asymmetrically in the sagittal plane, directed away from the lobule apex. On the basis of our anatomical and physiological characterization of this connection, we constructed a network model that robustly generated waves of activity that traveled along chains of connected Purkinje cells. Consistent with the model, we observed traveling waves of activity in Purkinje cells in sagittal slices from young mice that require GABAA receptor–mediated transmission and intact Purkinje cell axon collaterals. These traveling waves are absent in adult mice, suggesting they have a developmental role in wiring the cerebellar cortical microcircuit.

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Figure 1: Unitary synaptic connections between neighboring Purkinje cells.
Figure 2: Purkinje cell local axon collaterals establish synapses on other Purkinje cells.
Figure 3: Anatomical distribution of Purkinje cell axon collaterals and Purkinje-Purkinje synapses.
Figure 4: Purkinje cells synchronize in different phases depending on synaptic reversal potential.
Figure 5: Waves of activity in a network model of Purkinje cells.
Figure 6: Traveling waves in sagittal cerebellar slices.
Figure 7: Optical lesion of Purkinje axon collaterals abolishes traveling waves.
Figure 8: Purkinje cell-Purkinje cell connectivity and traveling waves are absent in older mice.

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References

  1. Ivry, R. Cerebellar timing systems. Int. Rev. Neurobiol. 41, 555–573 (1997).

    Article  CAS  Google Scholar 

  2. Chan-Palay, V. The recurrent collaterals of Purkinje cell axons: a correlated study of the rat's cerebellar cortex with electron microscopy and the Golgi method. Z. Anat. Entwicklungsgesch. 134, 200–234 (1971).

    Article  CAS  Google Scholar 

  3. Ramon y Cajal, S. Histologie du Systeme Nerveux de l'homme et des Vertebres (Maloine, Paris, 1911).

    Google Scholar 

  4. Larramendi, L.M. & Lemkey-Johnston, N. The distribution of recurrent Purkinje collateral synapses in the mouse cerebellar cortex: an electron microscopic study. J. Comp. Neurol. 138, 451–459 (1970).

    Article  CAS  Google Scholar 

  5. Hamori, J. & Szentagothai, J. Identification of synapses formed in the cerebellar cortex by Purkinje axon collaterals: an electron microscope study. Exp. Brain Res. 5, 118–128 (1968).

    Article  CAS  Google Scholar 

  6. De Camilli, P., Miller, P.E., Levitt, P., Walter, U. & Greengard, P. Anatomy of cerebellar Purkinje cells in the rat determined by a specific immunohistochemical marker. Neuroscience 11, 761–817 (1984).

    Article  CAS  Google Scholar 

  7. Orduz, D. & Llano, I. Recurrent axon collaterals underlie facilitating synapses between cerebellar Purkinje cells. Proc. Natl. Acad. Sci. USA 104, 17831–17836 (2007).

    Article  CAS  Google Scholar 

  8. Maex, R. & De Schutter, E. Oscillations in the cerebellar cortex: a prediction of their frequency bands. Prog. Brain Res. 148, 181–188 (2005).

    Article  Google Scholar 

  9. Sotelo, C. Cellular and genetic regulation of the development of the cerebellar system. Prog. Neurobiol. 72, 295–339 (2004).

    Article  CAS  Google Scholar 

  10. Gianola, S., Savio, T., Schwab, M.E. & Rossi, F. Cell-autonomous mechanisms and myelin-associated factors contribute to the development of Purkinje axon intracortical plexus in the rat cerebellum. J. Neurosci. 23, 4613–4624 (2003).

    Article  CAS  Google Scholar 

  11. Altman, J. Postnatal development of the cerebellar cortex in the rat. II. Phases in the maturation of Purkinje cells and of the molecular layer. J. Comp. Neurol. 145, 399–463 (1972).

    Article  CAS  Google Scholar 

  12. Feller, M.B. Spontaneous correlated activity in developing neural circuits. Neuron 22, 653–656 (1999).

    Article  CAS  Google Scholar 

  13. Ben-Ari, Y. Developing networks play a similar melody. Trends Neurosci. 24, 353–360 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Sekirnjak, C., Vissel, B., Bollinger, J., Faulstich, M. & du Lac, S. Purkinje cell synapses target physiologically unique brainstem neurons. J. Neurosci. 23, 6392–6398 (2003).

    Article  CAS  Google Scholar 

  16. Bali, B., Erdélyi, F., Szabó, G. & Kovacs, K.J. Visualization of stress-responsive inhibitory circuits in the GAD65-eGFP transgenic mice. Neurosci. Lett. 380, 60–65 (2005).

    Article  CAS  Google Scholar 

  17. Erdélyi, F. et al. GAD65-GFP transgenic mice expressing GFP in the GABAergic nervous system. FENS Abstr. 1, A011.3 (2003).

    Google Scholar 

  18. Raman, I.M. & Bean, B.P. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J. Neurosci. 17, 4517–4526 (1997).

    Article  CAS  Google Scholar 

  19. Häusser, M. & Clark, B.A. Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19, 665–678 (1997).

    Article  Google Scholar 

  20. Mittmann, W. & Häusser, M. Linking synaptic plasticity and spike output at excitatory and inhibitory synapses onto cerebellar Purkinje cells. J. Neurosci. 27, 5559–5570 (2007).

    Article  CAS  Google Scholar 

  21. Eilers, J., Plant, T.D., Marandi, N. & Konnerth, A. GABA-mediated Ca2+ signaling in developing rat cerebellar Purkinje neurones. J. Physiol. (Lond.) 536, 429–437 (2001).

    Article  CAS  Google Scholar 

  22. Vida, I., Bartos, M. & Jonas, P. Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates. Neuron 49, 107–117 (2006).

    Article  CAS  Google Scholar 

  23. Khaliq, Z.M., Gouwens, N.W. & Raman, I.M. The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: an experimental and modeling study. J. Neurosci. 23, 4899–4912 (2003).

    Article  CAS  Google Scholar 

  24. Firth, S.I., Wang, C.T. & Feller, M.B. Retinal waves: mechanisms and function in visual system development. Cell Calcium 37, 425–432 (2005).

    Article  CAS  Google Scholar 

  25. Yanik, M.F. et al. Neurosurgery: functional regeneration after laser axotomy. Nature 432, 822 (2004).

    Article  CAS  Google Scholar 

  26. Mejia-Gervacio, S. et al. Axonal speeding: shaping synaptic potentials in small neurons by the axonal membrane compartment. Neuron 53, 843–855 (2007).

    Article  CAS  Google Scholar 

  27. O'Donoghue, D.L., King, J.S. & Bishop, G.A. Physiological and anatomical studies of the interactions between Purkinje cells and basket cells in the cat's cerebellar cortex: evidence for a unitary relationship. J. Neurosci. 9, 2141–2150 (1989).

    Article  CAS  Google Scholar 

  28. Brody, C.D. Correlations without synchrony. Neural Comput. 11, 1537–1551 (1999).

    Article  CAS  Google Scholar 

  29. de la Rocha, J., Doiron, B., Shea-Brown, E., Josic, K. & Reyes, A. Correlation between neural spike trains increases with firing rate. Nature 448, 802–806 (2007).

    Article  CAS  Google Scholar 

  30. Hawkes, R. & Leclerc, N. Purkinje cell axon collateral distributions reflect the chemical compartmentation of the rat cerebellar cortex. Brain Res. 476, 279–290 (1989).

    Article  CAS  Google Scholar 

  31. Song, S., Sjöstrom, P.J., Reigl, M., Nelson, S. & Chklovskii, D.B. Highly nonrandom features of synaptic connectivity in local cortical circuits. PLoS Biol. 3, e68 (2005).

    Article  Google Scholar 

  32. Pedroarena, C.M. & Schwarz, C. Efficacy and short-term plasticity at GABAergic synapses between Purkinje and cerebellar nuclei neurons. J. Neurophysiol. 89, 704–715 (2003).

    Article  CAS  Google Scholar 

  33. Telgkamp, P. & Raman, I.M. Depression of inhibitory synaptic transmission between Purkinje cells and neurons of the cerebellar nuclei. J. Neurosci. 22, 8447–8457 (2002).

    Article  CAS  Google Scholar 

  34. Midtgaard, J. Stellate cell inhibition of Purkinje cells in the turtle cerebellum in vitro. J. Physiol. (Lond.) 457, 355–367 (1992).

    Article  CAS  Google Scholar 

  35. Pouzat, C. & Hestrin, S. Developmental regulation of basket/stellate cell → Purkinje cell synapses in the cerebellum. J. Neurosci. 17, 9104–9112 (1997).

    Article  CAS  Google Scholar 

  36. Reyes, A. & Sakmann, B. Developmental switch in the short-term modification of unitary EPSPs evoked in layer 2/3 and layer 5 pyramidal neurons of rat neocortex. J. Neurosci. 19, 3827–3835 (1999).

    Article  CAS  Google Scholar 

  37. Ben-Ari, Y. Excitatory actions of gaba during development: the nature of the nurture. Nat. Rev. Neurosci. 3, 728–739 (2002).

    Article  CAS  Google Scholar 

  38. Douglas, R.J. & Martin, K.A. Recurrent neuronal circuits in the neocortex. Curr. Biol. 17, R496–R500 (2007).

    Article  CAS  Google Scholar 

  39. Connors, B.W. & Telfeian, A.E. Dynamic properties of cells, synapses, circuits and seizures in neocortex. Adv. Neurol. 84, 141–152 (2000).

    CAS  PubMed  Google Scholar 

  40. Cohen, A.H. et al. Modelling of intersegmental coordination in the lamprey central pattern generator for locomotion. Trends Neurosci. 15, 434–438 (1992).

    Article  CAS  Google Scholar 

  41. de Solages, C. et al. High-frequency organization and synchrony of activity in the purkinje cell layer of the cerebellum. Neuron 58, 775–788 (2008).

    Article  CAS  Google Scholar 

  42. Geisler, C., Brunel, N. & Wang, X.J. Contributions of intrinsic membrane dynamics to fast network oscillations with irregular neuronal discharges. J. Neurophysiol. 94, 4344–4361 (2005).

    Article  Google Scholar 

  43. Lee, S.H., Blake, R. & Heeger, D.J. Traveling waves of activity in primary visual cortex during binocular rivalry. Nat. Neurosci. 8, 22–23 (2005).

    Article  CAS  Google Scholar 

  44. De Zeeuw, C.I., Hoebeek, F.E. & Schonewille, M. Causes and consequences of oscillations in the cerebellar cortex. Neuron 58, 655–658 (2008).

    Article  CAS  Google Scholar 

  45. Young, J.M. et al. Cortical reorganization consistent with spike timing, but not correlation, dependent plasticity. Nat. Neurosci. 10, 887–895 (2007).

    Article  CAS  Google Scholar 

  46. Kerschensteiner, D. & Wong, R.O. A precisely timed asynchronous pattern of ON and OFF retinal ganglion cell activity during propagation of retinal waves. Neuron 58, 851–858 (2008).

    Article  CAS  Google Scholar 

  47. Braitenberg, V. Functional interpretation of cerebellar histology. Nature 190, 539–540 (1961).

    Article  Google Scholar 

  48. Eccles, J.C., Szentagothai, J. & Ito, M. The Cerebellum as a Neuronal Machine (Springer-Verlag, Heidelberg, 1967).

    Book  Google Scholar 

  49. Oberdick, J., Baader, S.L. & Schilling, K. From zebra stripes to postal zones: deciphering patterns of gene expression in the cerebellum. Trends Neurosci. 21, 383–390 (1998).

    Article  CAS  Google Scholar 

  50. Rall, W. Theoretical significance of dendritic trees for neuronal input-output relations. in Neural Theory and Modeling (ed. Reiss, R.F. 73–97 (Stanford University Press, Stanford, California, USA, 1964).

    Google Scholar 

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Acknowledgements

We thank B. Clark, I. Duguid, F. Edwards, S. Ho, T. Ishikawa, M. London, E. Rancz, A. Roth and S. Smith for helpful discussions and for comments on the manuscript. We are grateful to S. du Lac, G. Szabó and F. Erdélyi for providing transgenic mice, to J. Gruendemann for providing tissue for reconstructions, to B. Clark for help with perfusions, and to L. Ramakrishnan and K. Powell for expert assistance with histology and Neurolucida reconstructions. This work was funded by a European Molecular Biology Organization Long-Term Fellowship and a Royal Society Dorothy Hodgkin Fellowship to A.J.W., a Feodor Lynen Fellowship of the Alexander von Humboldt Foundation to H.C., a European Young Investigator Award and a Wellcome Trust project grant to Z.N., a Marie-Curie Intra-European fellowship and Medical Research Council Career Development Award to P.J.S., and a Wellcome Trust Senior Research Fellowship and a grant from the Gatsby Foundation to M.H.

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Authors and Affiliations

  1. Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Alanna J Watt, Hermann Cuntz, Masahiro Mori, P Jesper Sjöström & Michael Häusser

  2. Department of Physiology and Biological Information, Dokkyo Medical University, Shimotsuga-gun, Tochigi, Japan

    Masahiro Mori

  3. Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

    Zoltan Nusser

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Correspondence to Alanna J Watt.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 – 7, Supplementary Table 1 and Supplementary Methods (PDF 6080 kb)

Supplementary Movie 1

Rotation of superimposed reconstructed Purkinje cells (n = 39) showing that axon collaterals lie predominantly in the sagittal plane (see Fig. 3b for scale bar). (MOV 2645 kb)

Supplementary Movie 2

Visualization of traveling waves in a model network of Purkinje cells connected by depolarizing synapses (Erev = −40 mV; see Fig. 5b). Cell location in the lobule is represented acoustically (low pitch = apex, high pitch = base of lobule). (MOV 2547 kb)

Supplementary Movie 3

Visualization of traveling waves in a model network of Purkinje cells connected by hyperpolarizing synapses (Erev = −80 mV; see Fig. 5c). Cell location in the lobule is represented acoustically (low pitch = apex, high pitch = base of lobule). (MOV 2561 kb)

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Watt, A., Cuntz, H., Mori, M. et al. Traveling waves in developing cerebellar cortex mediated by asymmetrical Purkinje cell connectivity. Nat Neurosci 12, 463–473 (2009). https://doi.org/10.1038/nn.2285

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