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

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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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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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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