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Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning

Nature Neuroscience volume 12, pages 1042–1049 (2009)Cite this article

Abstract

Although feedforward inhibition onto Purkinje cells was first documented 40 years ago, we understand little of how inhibitory interneurons contribute to cerebellar function in behaving animals. Using a mouse line (PC-Δγ2) in which GABAA receptor–mediated synaptic inhibition is selectively removed from Purkinje cells, we examined how feedforward inhibition from molecular layer interneurons regulates adaptation of the vestibulo-ocular reflex. Although impairment of baseline motor performance was relatively mild, the ability to adapt the phase of the vestibulo-ocular reflex and to consolidate gain adaptations was strongly compromised. Purkinje cells showed abnormal patterns of simple spikes, both during and in the absence of evoked compensatory eye movements. On the basis of modeling our experimental data, we propose that feedforward inhibition, by controlling the fine-scale patterns of Purkinje cell activity, enables the induction of plasticity in neurons of the cerebellar and vestibular nuclei.

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Figure 1: PC-Δγ2 mice show normal cerebellar morphology and synaptic organization.
Figure 2: Loss of fast synaptic inhibition from Purkinje cells in PC-Δγ2 mice.
Figure 3: PC-Δγ2 mice show altered parallel fiber–evoked and spontaneous simple-spike firing in vitro and unaltered parallel fiber–Purkinje cell LTP and LTD.
Figure 4: Motor learning is severely affected in PC-Δγ2 mice.
Figure 5: Temporal patterns of simple spike activities of floccular Purkinje cells are specifically affected in PC-Δγ2 mice during both compensatory eye movement behavior and spontaneous behavior.
Figure 6: Interpretation of VOR adaptation data using a distributed memory model.

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Acknowledgements

We thank L. Cheyne, D. Massie, M. Rutteman, R. Avila Freire, E. Dalm and J.v.d. Burg for their excellent technical assistance, and D. Andersson and L. Kelly for their participation in the initial electrophysiological studies. This work was supported by the J. Ernest Tait Estate Aberdeen (W.W.), a Medical Research Council program grant G0800399 (P.W. and W.W.), the Royal Society (P.W.), the Institute Pasteur-Fondazione Cenci Bolognetti (M.R.), a Wellcome Trust program grant (M.F.), Regione Piemonte (Ricerca Scientifica Applicata A218 and Ricerca Sanitaria Finalizzata 2006) and Compagnia di San Paolo (M.S.-P.), the Dutch Organization for Medical Sciences (C.I.D.Z.), Life Sciences (C.I.D.Z.), Senter (Neuro-Bsik, C.I.D.Z.), Prinses Beatrix Fonds (C.I.D.Z.), and the SENSOPAC (SENSOrimotor structuring of Perception and Action for Emerging Cognition) program of the European Community (C.I.D.Z.).

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Author notes

  1. Peer Wulff and Martijn Schonewille: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, UK

    Peer Wulff & William Wisden

  2. Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands

    Martijn Schonewille, Aleksandra Badura, Zhenyu Gao, Freek E Hoebeek & Chris I De Zeeuw

  3. Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Massimiliano Renzi & Mark Farrant

  4. Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin and National Institute of Neuroscience-Italy, Turin, Italy

    Laura Viltono & Marco Sassoè-Pognetto

  5. Netherlands Institute for Neuroscience, Royal Academy of Sciences, Amsterdam, The Netherlands

    Stijn van Dorp & Chris I De Zeeuw

  6. Division of Cell and Molecular Biology, Imperial College, London, UK

    William Wisden

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Contributions

P.W. developed the mouse model and helped coordinate the project. M.S. and A.B. designed and performed VOR experiments and in vivo electrophysiology. M.F. and M.R. designed, performed and analyzed the in vitro electrophysiology experiments. P.W., L.V. and M.S.-P. performed quantitative anatomical studies. Z.G. and F.E.H. performed LTP and LTD experiments. S.v.D. designed and implemented the model. W.W. initiated the project and coordinated collaborations between groups. C.I.D.Z. designed experiments and guided the project. P.W., M.S., M.R., S.v.D., W.W., M.F. and C.I.D.Z. co-wrote the manuscript.

Corresponding authors

Correspondence to William Wisden, Mark Farrant or Chris I De Zeeuw.

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Wulff, P., Schonewille, M., Renzi, M. et al. Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning. Nat Neurosci 12, 1042–1049 (2009). https://doi.org/10.1038/nn.2348

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