Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Spatiotemporal firing patterns in the cerebellum

Nature Reviews Neuroscience volume 12, pages 327–344 (2011)Cite this article

Subjects

Key Points

  • The olivocerebellar system is organized in modules and the cerebellar cortex is organized in Purkinje cell zones with common climbing-fibre inputs.

  • Neurons in the inferior olive are electrotonically coupled, and as a consequence the complex spikes of Purkinje cells have a tendency to occur in synchrony.

  • Neurons in the inferior olive show subthreshold oscillations and as a consequence the complex spikes of Purkinje cells have a tendency to occur rhythmically and to occur at specific time points.

  • Simple spikes can also show spatiotemporal patterns in that they can also occur in synchrony and in short regular patterns, which can be triggered by sensorimotor stimulation.

  • The simple-spike patterns and their intervals result from the intrinsic activity of Purkinje cells and their excitatory and inhibitory synaptic inputs, which are all subject to plastic processes.

  • The impact of complex-spike activity on simple-spike activity can be divided in acute natural impacts, heterosynaptic plasticity and global inhibition, all of which can have an impact on motor behaviour.

  • In many mouse mutants, changes in spatiotemporal patterns of Purkinje cell activity can be correlated with some deficit in motor performance, motor learning or motor consolidation.

  • The cerebellar nuclei are sensitive to synchronous Purkinje cell input.

  • Synchronous Purkinje cell input may result in rebound firing in cerebellar nucleus neurons.

  • The mossy- and climbing-fibre collaterals that impinge on cerebellar nuclei can undergo plasticity that is dependent on Purkinje cell input.

Abstract

Neurons are generally considered to communicate information by increasing or decreasing their firing rate. However, in principle, they could in addition convey messages by using specific spatiotemporal patterns of spiking activities and silent intervals. Here, we review expanding lines of evidence that such spatiotemporal coding occurs in the cerebellum, and that the olivocerebellar system is optimally designed to generate and employ precise patterns of complex spikes and simple spikes during the acquisition and consolidation of motor skills. These spatiotemporal patterns may complement rate coding, thus enabling precise control of motor and cognitive processing at a high spatiotemporal resolution by fine-tuning sensorimotor integration and coordination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Spike waveforms of the main cell types in olivocerebellar modules.
Figure 2: Complex-spike synchrony and rhythmicity.
Figure 3: Spatial and temporal patterns in simple-spike firing.
Figure 4: Synaptic plasticity affects simple-spike firing.
Figure 5: Read-out of patterns in cerebellar nuclei.

Similar content being viewed by others

References

  1. Williams, S. R. & Stuart, G. J. Role of dendritic synapse location in the control of action potential output. Trends Neurosci. 26, 147–154 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Tiesinga, P., Fellous, J. M. & Sejnowski, T. J. Regulation of spike timing in visual cortical circuits. Nature Rev. Neurosci. 9, 97–107 (2008).

    Article  CAS  Google Scholar 

  3. Saal, H. P., Vijayakumar, S. & Johansson, R. S. Information about complex fingertip parameters in individual human tactile afferent neurons. J. Neurosci. 29, 8022–8031 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kumbhani, R. D., Nolt, M. J. & Palmer, L. A. Precision, reliability, and information-theoretic analysis of visual thalamocortical neurons. J. Neurophysiol. 98, 2647–2663 (2007).

    Article  PubMed  Google Scholar 

  5. Markram, H., Lubke, J., Frotscher, M. & Sakmann, B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science 275, 213–215 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Albus, J. S. A theory of cerebellar function. Math. Biosci. 10, 25–61 (1971).

    Article  Google Scholar 

  7. McElvain, L. E., Bagnall, M. W., Sakatos, A. & du Lac, S. Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses. Neuron 68, 763–775 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Fujita, M. Simulation of adaptive modification of the vestibulo-ocular reflex with an adaptive filter model of the cerebellum. Biol. Cybern. 45, 207–214 (1982).

    Article  CAS  PubMed  Google Scholar 

  9. Ito, M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol. Rev. 81, 1143–1195 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Blazquez, P. M., Hirata, Y. & Highstein, S. M. The vestibulo-ocular reflex as a model system for motor learning: what is the role of the cerebellum? Cerebellum 3, 188–192 (2004).

    Article  PubMed  Google Scholar 

  11. Pasalar, S., Roitman, A. V., Durfee, W. K. & Ebner, T. J. Force field effects on cerebellar Purkinje cell discharge with implications for internal models. Nature Neurosci. 9, 1404–1411 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Lisberger, S. G. Internal models of eye movement in the floccular complex of the monkey cerebellum. Neuroscience 162, 763–776 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Walter, J. T. & Khodakhah, K. The advantages of linear information processing for cerebellar computation. Proc. Natl Acad. Sci. USA 106, 4471–4476 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Dean, P., Porrill, J., Ekerot, C. F. & Jorntell, H. The cerebellar microcircuit as an adaptive filter: experimental and computational evidence. Nature Rev. Neurosci. 11, 30–43 (2010).

    Article  CAS  Google Scholar 

  15. Jacobson, G. A., Rokni, D. & Yarom, Y. A model of the olivo-cerebellar system as a temporal pattern generator. Trends Neurosci. 31, 617–625 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Simpson, J. I., Wylie, D. R. & De Zeeuw, C. I. On climbing fiber signals and their consequence(s). Behav. Brain Sci. 19, 380–394 (1996).

    Google Scholar 

  17. Schmolesky, M. T., Weber, J. T., De Zeeuw, C. I. & Hansel, C. The making of a complex spike: ionic composition and plasticity. Ann. NY Acad. Sci. 978, 359–390 (2002).

    Article  PubMed  Google Scholar 

  18. Maruta, J., Hensbroek, R. A. & Simpson, J. I. Intraburst and interburst signaling by climbing fibers. J. Neurosci. 27, 11263–11270 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mathy, A. et al. Encoding of oscillations by axonal bursts in inferior olive neurons. Neuron 62, 388–399 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Clark, B. A., Monsivais, P., Branco, T., London, M. & Hausser, M. The site of action potential initiation in cerebellar Purkinje neurons. Nature Neurosci. 8, 137–139 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Khaliq, Z. M. & Raman, I. M. Axonal propagation of simple and complex spikes in cerebellar Purkinje neurons. J. Neurosci. 25, 454–463 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Llinás, R. & Sugimori, M. Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices. J. Physiol. 305, 197–213 (1980).

    Article  PubMed Central  PubMed  Google Scholar 

  23. McKay, B. E. et al. Climbing fiber discharge regulates cerebellar functions by controlling the intrinsic characteristics of purkinje cell output. J. Neurophysiol. 97, 2590–2604 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Davie, J. T., Clark, B. A. & Hausser, M. The origin of the complex spike in cerebellar Purkinje cells. J. Neurosci. 28, 7599–7609 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Sotelo, C., Llinás, R. & Baker, R. Structural study of inferior olivary nucleus of the cat: morphological correlates of electrotonic coupling. J. Neurophysiol. 37, 541–559 (1974).

    Article  CAS  PubMed  Google Scholar 

  26. Bal, T. & McCormick, D.A. Synchronized oscillations in the inferior olive are controlled by the hyperpolarization-activated cation current I(h). J. Neurophysiol. 77, 3145–3156 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Llinás, R. & Yarom, Y. Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J. Physiol. 315, 569–584 (1981).

    Article  PubMed Central  PubMed  Google Scholar 

  28. Long, M. A., Deans, M. R., Paul, D. L. & Connors, B. W. Rhythmicity without synchrony in the electrically uncoupled inferior olive. J. Neurosci. 22, 10898–10905 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. De Zeeuw, C. I. et al. Deformation of network connectivity in the inferior olive of connexin 36-deficient mice is compensated by morphological and electrophysiological changes at the single neuron level. J. Neurosci. 23, 4700–4711 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Llinás, R., Baker, R. & Sotelo, C. Electrotonic coupling between neurons in cat inferior olive. J. Neurophysiol. 37, 560–571 (1974).

    Article  PubMed  Google Scholar 

  31. De Zeeuw, C. I., Koekkoek, S. K. E., Wylie, D. R. W. & Simpson, J. I. Association between dendritic lamellar bodies and complex spike synchrony in the olivocerebellar system. J. Neurophysiol. 77, 1747–1758 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Blenkinsop, T. A. & Lang, E. J. Block of inferior olive gap junctional coupling decreases Purkinje cell complex spike synchrony and rhythmicity. J. Neurosci. 26, 1739–1748 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Van Der Giessen, R. S. et al. Role of olivary electrical coupling in cerebellar motor learning. Neuron 58, 599–612 (2008). The first demonstration that olivary coupling and complex-spike patterning are relevant for learning-dependent timing of movements.

    Article  CAS  PubMed  Google Scholar 

  34. Ozden, I., Sullivan, M. R., Lee, H. M. & Wang, S. S. Reliable coding emerges from coactivation of climbing fibers in microbands of cerebellar Purkinje neurons. J. Neurosci. 29, 10463–10473 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Welsh, J. P., Lang, E. J., Sugihara, I. & Llinás, R. Dynamic organization of motor control within the olivocerebellar system. Nature 374, 453–457 (1995). This study showed, using multiple unit recordings of ensembles of Purkinje cells during natural behaviour, that spatiotemporal patterns of complex-spike activity can be related to movements.

    Article  CAS  PubMed  Google Scholar 

  36. De Zeeuw, C. I. et al. Morphological correlates of bilateral synchrony in the rat cerebellar cortex. J. Neurosci. 16, 3412–3426 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bosman, L. W. et al. Encoding of whisker input by cerebellar Purkinje cells. J. Physiol. 588, 3757–3783 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Wylie, D. R., De Zeeuw, C. I. & Simpson, J. I. Temporal relations of the complex spike activity of Purkinje cell pairs in the vestibulocerebellum of rabbits. J. Neurosci. 15, 2875–2887 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mukamel, E. A., Nimmerjahn, A. & Schnitzer, M. J. Automated analysis of cellular signals from large-scale calcium imaging data. Neuron 63, 747–760 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Schultz, S. R., Kitamura, K., Post-Uiterweer, A., Krupic, J. & Hausser, M. Spatial pattern coding of sensory information by climbing fiber-evoked calcium signals in networks of neighboring cerebellar Purkinje cells. J. Neurosci. 29, 8005–8015 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. De Zeeuw, C. I. et al. Microcircuitry and function of the inferior olive. Trends Neurosci. 21, 391–400 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Lang, E. J., Sugihara, I. & Llinás, R. GABAergic modulation of complex spike activity by the cerebellar nucleoolivary pathway in rat. J. Neurophysiol. 76, 225–275 (1996). This study showed that the spatiotemporal patterns of complex-spike activity can be dynamically regulated by the GABAergic inputs to the inferior olive that are derived from the cerebellar nuclei.

    Article  Google Scholar 

  43. Flusberg, B. A. et al. High-speed, miniaturized fluorescence microscopy in freely moving mice. Nature Methods 5, 935–938 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Bennett, M. V., Spira, M. E. & Pappas, G. D. Properties of electrotonic junctions between embryonic cells of Fundulus. Dev. Biol. 29, 419–435 (1972).

    Article  CAS  PubMed  Google Scholar 

  45. Best, A. R. & Regehr, W. G. Inhibitory regulation of electrically coupled neurons in the inferior olive is mediated by asynchronous release of GABA. Neuron 62, 555–565 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Marshall, S. P. & Lang, E. J. Local changes in the excitability of the cerebellar cortex produce spatially restricted changes in complex spike synchrony. J. Neurosci. 29, 14352–14362 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Lang, E. J. Organization of olivocerebellar activity in the absence of excitatory glutamatergic input. J. Neurosci. 21, 1663–1675 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lang, E. J. Excitatory afferent modulation of complex spike synchrony. Cerebellum 2, 165–170 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Choi, S. et al. Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q.- and T-type calcium channels: a study in mutant mice. J. Physiol. 588, 3031–3043 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Khosrovani, S., Van Der Giessen, R. S., De Zeeuw, C. I. & De Jeu, M. T. In vivo mouse inferior olive neurons exhibit heterogeneous subthreshold oscillations and spiking patterns. Proc. Natl Acad. Sci. USA 104, 15911–15916 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Placantonakis, D. & Welsh, J. Two distinct oscillatory states determined by the NMDA receptor in rat inferior olive. J. Physiol. 534, 123–140 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Park, Y. G. et al. Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc. Natl Acad. Sci. USA 107, 10731–10736 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Leznik, E. & Llinás, R. Role of gap junctions in synchronized neuronal oscillations in the inferior olive. J. Neurophysiol. 94, 2447–2456 (2005).

    Article  PubMed  Google Scholar 

  54. Devor, A. & Yarom, Y. Generation and propagation of subthreshold waves in a network of inferior olivary neurons. J. Neurophysiol. 87, 3059–3069 (2002). One of the first optical imaging studies of the inferior olive, which demonstrated that olivary neurons can show phase-shifted activity in the form of propagating waves of activity within an oscillating region.

    Article  PubMed  Google Scholar 

  55. Llinás, R. R. Inferior olive oscillation as the temporal basis for motricity and oscillatory reset as the basis for motor error correction. Neuroscience 162, 797–804 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Jacobson, G. A., Lev, I., Yarom, Y. & Cohen, D. Invariant phase structure of olivo-cerebellar oscillations and its putative role in temporal pattern generation. Proc. Natl Acad. Sci. USA 106, 3579–3584 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. D'Angelo, E. & De Zeeuw, C. I. Timing and plasticity in the cerebellum: focus on the granular layer. Trends Neurosci. 32, 30–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Braitenberg, V. & Atwood, R. P. Morphological observations on the cerebellar cortex. J. Comp. Neurol. 109, 1–33 (1958).

    Article  CAS  PubMed  Google Scholar 

  59. Watt, A. J. et al. Traveling waves in developing cerebellar cortex mediated by asymmetrical Purkinje cell connectivity. Nature Neurosci. 12, 463–473 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Gao, W. et al. Optical imaging of long-term depression in the mouse cerebellar cortex in vivo. J. Neurosci. 23, 1859–1866 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cohen, D. & Yarom, Y. Patches of synchronized activity in the cerebellar cortex evoked by mossy-fiber stimulation: questioning the role of parallel fibers. Proc. Natl Acad. Sci. USA 95, 15032–15036 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Heck, D. H., Thach, W. T. & Keating, J. G. On-beam synchrony in the cerebellum as the mechanism for the timing and coordination of movement. Proc. Natl Acad. Sci. USA 104, 7658–7663 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bower, J. M. Model-founded explorations of the roles of molecular layer inhibition in regulating Purkinje cell responses in cerebellar cortex: more trouble for the beam hypothesis. Front. Cell Neurosci. 4, 1–16 (2010).

    Google Scholar 

  64. Bower, J. M. & Woolston, D. C. Congruence of spatial organization of tactile projections to granule cell and Purkinje cell layers of cerebellar hemispheres of the albino rat: vertical organization of cerebellar cortex. J. Neurophysiol. 49, 745–766 (1983).

    Article  CAS  PubMed  Google Scholar 

  65. Raman, I. M. & Bean, B. P. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J. Neurosci. 19, 1663–1674 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. Womack, M. D. & Khodakhah, K. Somatic and dendritic small-conductance calcium-activated potassium channels regulate the output of cerebellar purkinje neurons. J. Neurosci. 23, 2600–2607 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Miyashita, Y. & Nagao, S. Contribution of cerebellar intracortical inhibition to Purkinje cell response during vestibulo-ocular reflex of alert rabbits. J. Physiol. 351, 251–262 (1984).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Wada, N. et al. Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission. Proc. Natl Acad. Sci. USA 104, 16690–16695 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mittmann, W., Koch, U. & Hausser, M. Feed-forward inhibition shapes the spike output of cerebellar Purkinje cells. J. Physiol. 563, 369–378 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Wulff, P. et al. Synaptic inhibition of Purkinje cells mediates consolidation of vestibulo-cerebellar motor learning. Nature Neurosci. 12, 1042–1049 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Galliano, E. et al. Granule cell output mediates phase reversal learning and consolidation of gain learning by altering the regularity of Purkinje cell firing patterns. Soc. Neurosci. Abstr. 660.3 (Chicago, Illinois, 17–21 Oct 2009).

  74. Zhou, Y. D., Turner, T. J. & Dunlap, K. Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering. J. Physiol. 547, 497–507 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Hoebeek, F. E. et al. Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control. Neuron 45, 953–965 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Schonewille, M. et al. Purkinje cell-specific knockout of the protein phosphatase PP2B impairs potentiation and cerebellar motor learning. Neuron 67, 618–28 (2010). One of the first demonstrations that long-term potentiation at the parallel fibre–Purkinje cell synapse and intrinsic plasticity of Purkinje cells are relevant for cerebellar motor learning.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Loewenstein, Y. et al. Bistability of cerebellar Purkinje cells modulated by sensory stimulation. Nature Neurosci. 8, 202–211 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Schonewille, M. et al. Purkinje cells in awake behaving animals operate at the upstate membrane potential. Nature Neurosci. 9, 459–461; author reply 461 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Shin, S. L. et al. Regular patterns in cerebellar Purkinje cell simple spike trains. PLoS ONE 2, e485 (2007). One of the first studies to show patterning in simple-spike activity and to provide evidence for its functional relevance.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Koekkoek, S. K. et al. Cerebellar LTD and learning-dependent timing of conditioned eyelid responses. Science 301, 1736–1739 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Jorntell, H. & Ekerot, C. F. Reciprocal bidirectional plasticity of parallel fiber receptive fields in cerebellar Purkinje cells and their afferent interneurons. Neuron 34, 797–806 (2002). This study was one of the first to show that changes in the receptive fields of Purkinje cells and molecular layer interneurons are reciprocal and driven by climbing-fibre input.

    Article  CAS  PubMed  Google Scholar 

  82. Szapiro, G. & Barbour, B. Multiple climbing fibers signal to molecular layer interneurons exclusively via glutamate spillover. Nature Neurosci. 10, 735–742 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Sato, Y., Miura, A., Fushika, H. & Kawasaki, T. Short-term modulation of cerebellar purkinjecell activity after spontaneous climbing fiber input. J. Neurophysiol. 68, 2051–2062 (1992).

    Article  CAS  PubMed  Google Scholar 

  84. Schiffmann, S. N. et al. Impaired motor coordination and Purkinje cell excitability in mice lacking calretinin. Proc. Natl Acad. Sci. USA 96, 5257–5262 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yakhnitsa, V. & Barmack, N. H. Antiphasic Purkinje cell responses in mouse uvula-nodulus are sensitive to static roll-tilt and topographically organized. Neuroscience 143, 615–626 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. McDevitt, C. J., Ebner, T. J. & Bloedel, J. R. The changes in Purkinje cell simple spike activity following spontaneous climbing fiber inputs. Brain Res. 237, 484–491 (1982).

    Article  CAS  PubMed  Google Scholar 

  87. Van der Ende, B. et al. Complex spike induced simple spike interactions beyond the climbing fiber pause in cerebellar Purkinje cells of anaesthetized and awake behaving mice. FENS Abstr. 192.56 (Amsterdam, The Netherlands, 3–7 Jul 2010).

  88. Schwarz, C. & Welsh, J. P. Dynamic modulation of mossy fiber system throughput by inferior olive synchrony: a multielectrode study of cerebellar cortex activated by motor cortex. J. Neurophysiol. 86, 2489–2504 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Ito, M. & Kano, M. Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci. Lett. 33, 253–258 (1982).

    Article  CAS  PubMed  Google Scholar 

  90. Hansel, C. et al. αlphaCaMKII Is essential for cerebellar LTD and motor learning. Neuron 51, 835–843 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Schonewille, M. et al. Re-evaluating the role of LTD in cerebellar motor learning. Neuron 70, 43–50 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Steuber, V. et al. Cerebellar LTD and pattern recognition by Purkinje cells. Neuron 54, 121–136 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Tanimura, A. et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase αlpha mediates retrograde suppression of synaptic transmission. Neuron 65, 320–327 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Brenowitz, S. D. & Regehr, W. G. Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron 45, 419–431 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Bidoret, C., Ayon, A., Barbour, B. & Casado, M. Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule. Proc. Natl Acad. Sci. USA 106, 14126–14131 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kano, M., Rexhausen, U., Dreessen, J. & Konnerth A. Synaptic excitation produces a long-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells. Nature 356, 601–604 (1992). This study showed for the first time a form of neural plasticity in which activation of an excitatory synaptic input can induce potentiation of inhibitory synaptic signals to the same cell. This form of synaptic plasticity has been somewhat neglected in the cerebellar field owing to the dominance of LTD at the parallel fibre–Purkinje cell synapse, but could in principle be at least as important.

    Article  CAS  PubMed  Google Scholar 

  97. Coesmans, M., Weber, J. T., De Zeeuw, C. I. & Hansel, C. Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control. Neuron 44, 691–700 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Wang, X., Chen, G., Gao, W. & Ebner, T. Long-term potentiation of the responses to parallel fiber stimulation in mouse cerebellar cortex in vivo. Neuroscience 162, 713–722 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Belmeguenai, A. et al. Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells. J. Neurosci. 30, 13630–13643 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Atluri, P. P. & Regehr, W. G. Determinants of the time course of facilitation at the granule cell to Purkinje cell synapse. J. Neurosci. 16, 5661–5671 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Batchelor, A. M. & Garthwaite, J. Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway. Nature 385, 74–77 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Kim, S. J. et al. Transient upregulation of postsynaptic IP3-gated Ca release underlies short-term potentiation of metabotropic glutamate receptor 1 signaling in cerebellar Purkinje cells. J. Neurosci. 28, 4350–4355 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Jorntell, H. & Ekerot, C. F. Receptive field plasticity profoundly alters the cutaneous parallel fiber synaptic input to cerebellar interneurons in vivo. J. Neurosci. 23, 9620–9631 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Rancillac, A. & Crepel, F. Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum. J. Physiol. 554, 707–720 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Bao, J., Reim, K. & Sakaba, T. Target-dependent feedforward inhibition mediated by short-term synaptic plasticity in the cerebellum. J. Neurosci. 30, 8171–8179 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Medina, J. F. & Lisberger, S. G. Links from complex spikes to local plasticity and motor learning in the cerebellum of awake-behaving monkeys. Nature Neurosci. 11, 1185–1192 (2008). Following trial-by-trial analysis of Purkinje cell responses in awake, behaving animals, this study shows that the presence of a complex spike on one learning trial can be linked to a substantial suppression of simple-spike responses on the subsequent trial, at a time when behavioural learning is expressed.

    Article  CAS  PubMed  Google Scholar 

  107. Ebner, T. J., Johnson, M. T., Roitman, A. & Fu, Q. What do complex spikes signal about limb movements? Ann. NY Acad. Sci. 978, 205–218 (2002).

    Article  PubMed  Google Scholar 

  108. Jirenhed, D. A., Bengtsson, F. & Hesslow, G. Acquisition, extinction, and reacquisition of a cerebellar cortical memory trace. J. Neurosci. 27, 2493–2502 (2007). These authors showed that paired stimulation of mossy fibres and climbing fibres causes gradual acquisition of an inhibitory response in simple-spike firing, and that the response latency varies with the inter-stimulus interval, raising the possibility that several basic behavioural phenomena in eyeblink conditioning can be explained at the level of the Purkinje cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Stratton, S. E., Lorden, J. F., Mays, L. E. & Oltmans, G. A. Spontaneous and harmaline-stimulated Purkinje cell activity in rats with a genetic movement disorder. Journal of Neuroscience 8, 3327–3336 (1988).

    Article  CAS  PubMed  Google Scholar 

  110. Montarolo, P. G., Palestini, M. & Strata, P. The inhibitory effect of the olivocerebellar input on the cerebellar Purkinje cells in the rat. J. Physiol. 332, 187–202 (1982).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. McKay, B. E. & Turner, R. W. Kv3 K+ channels enable burst output in rat cerebellar Purkinje cells. Eur.opean J. Neurosci. 20, 729–739 (2004).

    Article  CAS  Google Scholar 

  113. Walter, J. T., Alvina, K., Womack, M. D., Chevez, C. & Khodakhah, K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nature Neurosci. 9, 389–397 (2006). This study shows that the irregular pacemaking in ataxic P/Q-channel mutant mice is caused by reduced activation of calcium-activated potassium (K(Ca)) channels and can be reversed by pharmacologically increasing their activity. These data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that K(Ca) channels may constitute a potential therapeutic target in EA2.

    Article  CAS  PubMed  Google Scholar 

  114. Alvina, K. & Khodakhah, K. KCa channels as therapeutic targets in episodic ataxia type-2. J.Neurosci 30, 7249–7257 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Barmack, N. H. & Yakhnitsa, V. Functions of interneurons in mouse cerebellum. J. Neurosci. 28, 1140–1152 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lisberger, S. G. & Fuchs, A. F. Role of primate flocculus during rapid behavioral modification of vestibuloocular reflex. II. Mossy fiber firing patterns during horizontal head rotation and eye movement. J. Neurophysiol. 41, 764–777 (1978).

    Article  CAS  PubMed  Google Scholar 

  117. De Zeeuw, C. I., Wylie, D. R., DiGiorgi, P. L. & Simpson, J. I. Projections of individual Purkinje cells of identified zones in the flocculus to the vestibular and cerebellar nuclei in the rabbit. J. Comp. Neurol. 349, 428–447 (1994).

    Article  CAS  PubMed  Google Scholar 

  118. Voogd, J., Schraa-Tam, C. K., van der Geest, J. N. & De Zeeuw, C. I. Visuomotor cerebellum in human and nonhuman primates. Cerebellum, 31 Aug 2010 (doi:10.1007/s12311-010-0204-7).

    Article  Google Scholar 

  119. Renier, N. et al. Genetic dissection of the function of hindbrain axonal commissures. PLoS Biol. 8, e1000325 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Badura, A. et al. Disruption in cerebellar circuitry causes more profound impairment than having no cerebellar output at all. Soc. Neurosci. Abstr. 786.20 (San Diego, California, 13–17 Nov 2010).

  121. Chan-Palay, V. Cerebellar Dentate Nucleus: Organization, Cytology and Transmitters (Springer-Verlag, Berlin, 1977).

    Book  Google Scholar 

  122. De Zeeuw, C. I. & Berrebi, A. S. Postsynaptic targets of Purkinje cell terminals in the cerebellar and vestibular nuclei of the rat. Eur. J. Neurosci. 7, 2322–2333 (1995).

    Article  CAS  PubMed  Google Scholar 

  123. Gauck, V. & Jaeger, D. The control of rate and timing of spikes in the deep cerebellar nuclei by inhibition. J. Neurosci. 20, 3006–3016 (2000). This study shows that the timing of individual spikes in cerebellar-nucleus neurons can be controlled precisely by short decreases in the inhibitory conductance that are the consequence of synchronization between many inputs, and that the spike rate of these neurons can be controlled by both the rate of inhibitory inputs and synchronicity present in the inhibitory inputs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Akam, T. & Kullmann, D. M. Oscillations and filtering networks support flexible routing of information. Neuron 67, 308–320 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Monsivais, P., Clark, B. A., Roth, A. & Hausser, M. Determinants of action potential propagation in cerebellar Purkinje cell axons. J. Neurosci. 25, 464–472 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hoebeek, F. E., Witter, L., Ruigrok, T. J. & De Zeeuw, C. I. Differential olivo-cerebellar cortical control of rebound activity in the cerebellar nuclei. Proc. Natl Acad. Sci. USA 107, 8410–8415 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Uusisaari, M., Obata, K. & Knopfel, T. Morphological and electrophysiological properties of GABAergic and non-GABAergic cells in the deep cerebellar nuclei. J. Neurophysiol. 97, 901–911 (2007). One of the first demonstrations that the GABAergic and non-GABAergic neurons in the cerebellar nuclei show distinct electrophysiological features, which has major implications for the way in which the nuclei can differentially influence activity of neurons in the inferior olive and motor related brainstem nulcei downstream.

    Article  CAS  PubMed  Google Scholar 

  128. Medina, J. F., Nores, W. L. & Mauk, M. D. Inhibition of climbing fibres is a signal for the extinction of conditioned eyelid responses. Nature 416, 330–333 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Llinás, R. & Sasaki, K. The functional organization of the olivocerebellar system as examined by multiple Purkinje cell recordings. Eur. J. Neurosci. 1, 587–602 (1989).

    Article  PubMed  Google Scholar 

  130. De Zeeuw, C. I., Holstege, J. C., Ruigrok, T. J. & Voogd J. Ultrastructural study of the GABAergic, cerebellar, and mesodiencephalic innervation of the cat medial accessory olive: anterograde tracing combined with immunocytochemistry. J. Comp. Neurol. 284, 12–35 (1989).

    Article  CAS  PubMed  Google Scholar 

  131. Bagnall, M. W. et al. Glycinergic projection neurons of the cerebellum. J. Neurosci. 29, 10104–10110 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Sawyer, S. F., Young, S. J., Groves, P. M. & Tepper, J. M. Cerebellar-responsive neurons in the thalamic ventroanterior-ventrolateral complex of rats: in vivo electrophysiology. Neuroscience 63, 711–724 (1994).

    Article  CAS  PubMed  Google Scholar 

  133. Kitazawa, S., Kimura, T. & Yin, P. B. Cerebellar complex spikes encode both destinations and errors in arm movements. Nature 392, 494–497 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Sekirnjak, C. & du Lac, S. Intrinsic firing dynamics of vestibular nucleus neurons. J. Neurosci. 22, 2083–2095 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Morishita, W. & Sastry, B. R. Postsynaptic mechanisms underlying long-term depression of GABAergic transmission in neurons of the deep cerebellar nuclei. J. Neurophysiol. 76, 59–68 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. Ouardouz, M. & Sastry, B. R. Mechanisms underlying LTP of inhibitory synaptic transmission in the deep cerebellar nuclei. J. Neurophysiol. 84, 1414–1421 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. Zheng, N. & Raman, I. M. Ca currents activated by spontaneous firing and synaptic disinhibition in neurons of the cerebellar nuclei. J. Neurosci. 29, 9826–9838 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Suter, K. J. & Jaeger, D. Reliable control of spike rate and spike timing by rapid input transients in cerebellar stellate cells. Neuroscience 124, 305–317 (2004).

    Article  CAS  PubMed  Google Scholar 

  139. 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  PubMed  PubMed Central  Google Scholar 

  140. 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  PubMed  Google Scholar 

  141. Borst, J. G. The low synaptic release probability in vivo. Trends Neurosci. 33, 259–266 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. De Schutter, E. & Steuber, V. Patterns and pauses in Purkinje cell simple spike trains: experiments, modeling and theory. Neuroscience 162, 816–826 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. 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  PubMed  Google Scholar 

  144. Pugh, J. R. & Raman, I. M. Potentiation of mossy fiber EPSCs in the cerebellar nuclei by NMDA receptor activation followed by postinhibitory rebound current. Neuron 51, 113–123 (2006). The authors showed NMDA receptor-dependent potentiation of cerebellar-nucleus neurons that occurred when the mossy-fibre stimulation preceded a postinhibitory rebound depolarization, suggesting that Purkinje cell inhibition can guide the strengthening of excitatory synapses in the cerebellar nuclei and that the rebound may facilitate this form of plasticity.

    Article  CAS  PubMed  Google Scholar 

  145. Zheng, N. & Raman, I. M. Synaptic inhibition, excitation, and plasticity in neurons of the cerebellar nuclei. Cerebellum 9, 56–66 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  146. Pugh, J. R. & Raman, I. M. Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition. J. Neurosci. 28, 10549–10560 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Voogd, J., Pardoe, J., Ruigrok, T. J. & Apps, R. The distribution of climbing and mossy fiber collateral branches from the copula pyramidis and the paramedian lobule: congruence of climbing fiber cortical zones and the pattern of zebrin banding within the rat cerebellum. J. Neurosci. 23, 4645–4656 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Boele, H. J., Koekkoek, S. K. & De Zeeuw, C. I. Cerebellar and extracerebellar involvement in mouse eyeblink conditioning: the ACDC model. Front. Cell Neurosci. 3, 1–13 (2010).

    Article  Google Scholar 

  149. Schwartz, A. B., Ebner, T. J. & Bloedel, J. R. Responses of interposed and dentate neurons to perturbations of the locomotor cycle. Exp. Brain Res. 67, 323–338 (1987).

    Article  CAS  PubMed  Google Scholar 

  150. Aizenman, C. D. & Linden, D. J. Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons. Nature Neurosci. 3, 109–111 (2000). One of the first demonstrations that neurons in the cerebellar nuclei can show — in addition to use-dependent alterations in synaptic strength — persistent increases in their intrinsic excitability.

    Article  CAS  PubMed  Google Scholar 

  151. Nelson, A. B., Krispel, C. M., Sekirnjak, C. & du Lac, S. Long-lasting increases in intrinsic excitability triggered by inhibition. Neuron 40, 609–620 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Sejnowski, T. J. & Paulsen, O. Network oscillations: emerging computational principles. J. Neurosci. 26, 1673–1676 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Tiesinga, P. H., Fellous, J. M., Salinas, E., Jose, J. V. & Sejnowski, T. J. Inhibitory synchrony as a mechanism for attentional gain modulation. J. Physiol. Paris 98, 296–314 (2004).

    Article  PubMed  Google Scholar 

  154. Otmakhov, N., Shirke, A. M. & Malinow, R. Measuring the impact of probabilistic transmission on neuronal output. Neuron 10, 1101–1111 (1993).

    Article  CAS  PubMed  Google Scholar 

  155. Markram, H., Lubke, J., Frotscher, M., Roth, A. & Sakmann, B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. J. Physiol. 500 (Pt 2), 409–440 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Sanchez-Campusano, R., Gruart, A. & Delgado-Garcia, J. M. Dynamic associations in the cerebellar-motoneuron network during motor learning. J. Neurosci. 29, 10750–10763 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. De Zeeuw, C. I., Wylie, D. R., Stahl, J. S. & Simpson, J. I. Phase relations of Purkinje cells in the rabbit flocculus during compensatory eye Movements. J. of Neurophysiol. 74, 2051–2063 (1995).

    Article  CAS  Google Scholar 

  158. Mugnaini, E., Sekerkova, G. & Martina, M. The unipolar brush cell: a remarkable neuron finally receiving deserved attention. Brain Res. Rev. 66, 220–245 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Simpson, J. I., Hulscher, H. C., Sabel-Goedknegt, E. & Ruigrok, T. J. Between in and out: linking morphology and physiology of cerebellar cortical interneurons. Prog. Brain Res. 148, 329–340 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Palay, S. L. & Chan-Palay, V. Cerebellar Cortex: Cytology and Organization (Springer Verlag, Berlin, Heidelberg, New York, 1974).

    Book  Google Scholar 

  161. Sillitoe, R. V., Chung, S. H., Fritschy, J. M., Hoy, M. & Hawkes, R. Golgi cell dendrites are restricted by Purkinje cell stripe boundaries in the adult mouse cerebellar cortex. J. Neurosci. 28, 2820–2826 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Dino, M. R., Schuerger, R. J., Liu, Y., Slater, N. T. & Mugnaini, E. Unipolar brush cell: a potential feedforward excitatory interneuron of the cerebellum. Neuroscience 98, 625–636 (2000).

    Article  CAS  PubMed  Google Scholar 

  163. Arenz, A., Silver, R. A., Schaefer, A. T. & Margrie, T. W. The contribution of single synapses to sensory representation in vivo. Science 321, 977–980 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  164. Garwicz, M. & Andersson, G. Spread of synaptic activity along parallel fibres in cat cerebellar anterior lobe. Exp. Brain Res. 88, 615–622 (1992).

    Article  CAS  PubMed  Google Scholar 

  165. Fletcher, C. F. et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87, 607–617 (1996).

    Article  CAS  PubMed  Google Scholar 

  166. Matsushita, K. et al. Bidirectional alterations in cerebellar synaptic transmission of tottering and rolling Ca2+ channel mutant mice. J. Neurosci. 22, 4388–4398 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mintz, I. M. & Bean, B. P. GABAB receptor inhibition of P-type Ca2+ channels in central neurons. Neuron 10, 889–898 (1993).

    Article  CAS  PubMed  Google Scholar 

  168. Gao, Z. et al. Increased calcium influx in CACNA1A S218L knock-in mice induces irregular Purkinje cell firing patterns. Soc. Neurosci. Abstr., 660.1 (Chicago, Illinois, 17–21 Oct 2009).

  169. van den Maagdenberg, A. M. et al. High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann. Neurol. 67, 285–298 (2010).

    Article  CAS  Google Scholar 

  170. Llinás, R. & Mühlethaler, M. Electrophysiology of guinea-pig cerebellar nuclear cells in the in vitro brain stem-cerebellar preparation. J. Physiol. 404, 241–258 (1988).

    Article  PubMed Central  PubMed  Google Scholar 

  171. Wetmore, D. Z., Mukamel, E. A. & Schnitzer, M. J. Lock-and-key mechanisms of cerebellar memory recall based on rebound currents. J. Neurophysiol. 100, 2328–2347 (2008).

    Article  PubMed  Google Scholar 

  172. Kistler, W. M., van Hemmen, J. L. & De Zeeuw, C. I. Time window control: a model for cerebellar function based on synchronization, reverberation, and time slicing. Prog. Brain Res. 124, 275–297 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Gruart, A., Blázquez, P., Pastor, A.M. & Delgado-García, J.M. Very short-term potentiation of climbing fiber effects on deep cerebellar nuclei neurons by conditioning stimulation of mossy fiber afferents. Exp. Brain Res. 101, 173–177 (1994).

    Article  CAS  PubMed  Google Scholar 

  174. Alvina, K., Walter, J. T., Kohn, A., Ellis-Davies, G. & Khodakhah, K. Questioning the role of rebound firing in the cerebellum. Nature Neurosci. 11, 1256–1258 (2008).

    Article  CAS  PubMed  Google Scholar 

  175. Tadayonnejad, R. et al. Rebound discharge in deep cerebellar nuclear neurons in vitro. Cerebellum, 9, 352–374 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  176. Witter, L., De Zeeuw, C. I., Ruigrok, T. J. & Hoebeek, F. E. The cerebellar nuclei take center stage. Cerebellum 29 Jan 2011 (doi:10.1007/s12311-010-0245-y).

    Article  PubMed  Google Scholar 

  177. Aizenman, C. D., Manis, P. B. & Linden, D. J. Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse. Neuron 21, 827–835 (1998).

    Article  CAS  PubMed  Google Scholar 

  178. Aizenman, C. D. & Linden, D. J. Regulation of the rebound depolarization and spontaneous firing patterns of deep nuclear neurons in slices of rat cerebellum. J. Neurophysiol. 82, 1697–1709 (1999).

    Article  CAS  PubMed  Google Scholar 

  179. Czubayko, U., Sultan, F., Thier, P. & Schwarz, C. Two types of neurons in the rat cerebellar nuclei as distinguished by membrane potentials and intracellular fillings. J. Neurophysiol. 85, 2017–2029 (2001).

    Article  CAS  PubMed  Google Scholar 

  180. Zhang, W., Shin, J. H. & Linden, D. J. Persistent changes in the intrinsic excitability of rat deep cerebellar nuclear neurones induced by EPSP or IPSP bursts. J. Physiol. 561, 703–719 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  181. Raman, I. M., Gustafson, A. E. & Padgett, D. Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J. Neurosci. 20, 9004–9016 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Sangrey, T. & Jaeger, D. Analysis of distinct short and prolonged components in rebound spiking of deep cerebellar nucleus neurons. Eur. J. Neurosci. 32, 1646–1657 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  183. Alvina, K., Ellis-Davies, G. & Khodakhah, K. T-type calcium channels mediate rebound firing in intact deep cerebellar neurons. Neuroscience 158, 635–641 (2009).

    Article  CAS  PubMed  Google Scholar 

  184. Molineux, M. L. et al. Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. Proc. Natl Acad. Sci. USA 103, 5555–5560 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Molineux, M. L. et al. Ionic factors governing rebound burst phenotype in rat deep cerebellar neurons. J. Neurophysiol. 100, 2684–2701 (2008).

    Article  CAS  PubMed  Google Scholar 

  186. Tadayonnejad, R., Mehaffey, W. H., Anderson, D. & Turner, R. W. Reliability of triggering postinhibitory rebound bursts in deep cerebellar neurons. Channels (Austin) 3, 149–155 (2009).

    Article  CAS  Google Scholar 

  187. Aksenov, D., Serdyukova, N., Irwin, K. & Bracha, V. GABA neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity. J. Neurophysiol. 91, 719–727 (2004).

    Article  CAS  PubMed  Google Scholar 

  188. Hepp, K., Henn, V. & Jaeger, J. Eye movement related neurons in the cerebellar nuclei of the alert monkey. Exp. Brain Res. 45, 253–264 (1982).

    CAS  PubMed  Google Scholar 

  189. MacKay, W. A. Unit activity in the cerebellar nuclei related to arm reaching movements. Brain Res. 442, 240–254 (1988).

    Article  CAS  PubMed  Google Scholar 

  190. Chubb, M. C. & Fuchs, A. F. Contribution of y group of vestibular nuclei and dentate nucleus of cerebellum to generation of vertical smooth eye movements. J. Neurophysiol. 48, 75–99 (1982).

    Article  CAS  PubMed  Google Scholar 

  191. Gardner, E. P. & Fuchs, A. F. Single-unit responses to natural vestibular stimuli and eye movements in deep cerebellar nuclei of the alert rhesus monkey. J. Neurophysiol. 38, 627–649 (1975).

    Article  CAS  PubMed  Google Scholar 

  192. Ohtsuka, K. & Noda, H. Saccadic burst neurons in the oculomotor region of the fastigial nucleus of macaque monkeys. J. Neurophysiol. 65, 1422–1434 (1991).

    Article  CAS  PubMed  Google Scholar 

  193. Armstrong, D. M., Cogdell, B. & Harvey, R. J. Response of interpositus neurones to nerve stimulation in chloralose anesthetized cats. Brain Res. 55, 461–466 (1973).

    Article  CAS  PubMed  Google Scholar 

  194. Armstrong, D. M., Cogdell, B. & Harvey, R. Effects of afferent volleys from the limbs on the discharge patterns of interpositus neurones in cats anaesthetized with alpha-chloralose. J. Physiol. 248, 489–517 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  195. Chen, F. P. & Evinger, C. Cerebellar modulation of trigeminal reflex blinks: interpositus neurons. J. Neurosci. 26, 10569–10576 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Rowland, N. C. & Jaeger, D. Coding of tactile response properties in the rat deep cerebellar nuclei. J. Neurophysiol. 94, 1236–1251 (2005).

    Article  PubMed  Google Scholar 

  197. Rowland, N. C. & Jaeger, D. Responses to tactile stimulation in deep cerebellar nucleus neurons result from recurrent activation in multiple pathways. J. Neurophysiol. 99, 704–717 (2008).

    Article  PubMed  Google Scholar 

  198. Eccles, J. C., Sabah, N. H. & Taborikova, H. Excitatory and inhibitory responses of neurones of the cerebellar fastigial nucleus. Exp. Brain Res. 19, 61–77 (1974).

    Article  CAS  PubMed  Google Scholar 

  199. Alvina, K. & Khodakhah, K. Selective regulation of spontaneous activity of neurons of the deep cerebellar nuclei by N.-type calcium channels in juvenile rats. J. Physiol. 586, 2523–2538 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  200. Feng, S. S. & Jaeger, D. The role of SK calcium-dependent potassium currents in regulating the activity of deep cerebellar nucleus neurons: a dynamic clamp study. Cerebellum 7, 542–546 (2008).

    Article  CAS  PubMed  Google Scholar 

  201. Chadderton, P., Margrie, T. W. & Hausser, M. Integration of quanta in cerebellar granule cells during sensory processing. Nature 428, 856–860 (2004). One of the first whole-cell patch-clamp recording studies of the cerebellar cortex in vivo , which showed that granule cells have a low ongoing firing rate and that spike bursts that are triggered by sensory stimulation can be evoked by only a few quantal EPSCs. These results reveal that the input layer of the cerebellum balances exquisite sensitivity with a high signal-to-noise ratio.

    Article  CAS  PubMed  Google Scholar 

  202. Boele, H. J., Koekkoek, S. K., De Zeeuw, C. I. & Ruigrok, T. J. Are changes in 'hard-wiring' involved in cerebellar motor learning?. Soc. Neurosc. Abstr. 660.20 (Chicago, Illinois, 17–21 Oct 2009).

  203. Ahissar, E., Sosnik, R. & Haidarliu, S. Transformation from temporal to rate coding in a somatosensory thalamocortical pathway. Nature 406, 302–306 (2000).

    Article  CAS  PubMed  Google Scholar 

  204. De Zeeuw, C. I. et al. Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron 20, 495–508 (1998).

    Article  CAS  PubMed  Google Scholar 

  205. Goossens, H. H. et al. Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long-term depression. Eur. J. Neurosci. 19, 687–697 (2004).

    Article  CAS  PubMed  Google Scholar 

  206. Goossens, J. et al. Expression of protein kinase C inhibitor blocks cerebellar long-term depression without affecting Purkinje cell excitability in alert mice. J. Neurosci. 21, 5813–5823 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Chen, C. et al. Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC γamma mutant mice. Cell 83, 1233–1242 (1995).

    Article  CAS  PubMed  Google Scholar 

  208. Kano, M. et al. Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron 18, 71–79 (1997).

    Article  CAS  PubMed  Google Scholar 

  209. Aiba, A. et al. Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79, 377–388 (1994).

    Article  CAS  PubMed  Google Scholar 

  210. Ichise, T. et al. mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288, 1832–1835 (2000).

    Article  CAS  PubMed  Google Scholar 

  211. Sausbier, M. et al. Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc. Natl Acad. Sci. USA 101, 9474–9478 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Chen, X. et al. Disruption of the olivo-cerebellar circuit by Purkinje neuron-specific ablation of BK channels. Proc. Natl Acad. Sci. USA 107, 12323–12328 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Cheron, G. et al. BK channels control cerebellar Purkinje and Golgi cell rhythmicity in vivo. PLoS ONE 4, e7991 (2009).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  214. van Woerden, G. M. et al. βetaCaMKII controls the direction of plasticity at parallel fiber-Purkinje cell synapses. Nature Neurosci. 12, 823–825 (2009).

    Article  CAS  PubMed  Google Scholar 

  215. Siggins, G. R., Henriksen, S. J. & Landis, S. C. Electrophysiology of Purkinje neurons in the weaver mouse: iontophoresis of neurotransmitters and cyclic nucleotides, and stimulation of the nucleus locus coeruleus. Brain Res. 114, 53–69 (1976).

    Article  CAS  PubMed  Google Scholar 

  216. Crepel, F. & Mariani, J. Multiple innervation of Purkinje cells by climbing fibers in the cerebellum of the weaver mutant mouse. J. Neurobiol. 7, 579–582 (1976).

    Article  CAS  PubMed  Google Scholar 

  217. Coesmans, M. et al. Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Ann. Neurol. 53, 325–336 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We kindly thank the following organizations for their financial support: the Netherlands Organization for Medical Sciences (ZonMw) to C.I.D.Z., the Netherlands Organization for Life Sciences (ALW) to C.I.D.Z., F.E.H., M.S. and S.K.K., Fonds Economische Stuurversterking (NeuroBasic project) to C.I.D.Z., the Erasmus University Fellowship to F.E.H. and M.S., the Prinses Beatrix Fonds to C.I.D.Z., and the SENSOPAC (sensorimotor structuring of perception and action for emergent cognition), CEREBNET and C7 programs of the European Community to C.I.D.Z. We also thank our laboratory members for valuable discussions.

Author information

Author notes

  1. Chris I. De Zeeuw, Freek E. Hoebeek, Laurens W. J. Bosman, Martijn Schonewille and Laurens Witter: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Neuroscience, Erasmus Medical Center, Rotterdam, 3000DR, The Netherlands

    Chris I. De Zeeuw, Freek E. Hoebeek, Laurens W. J. Bosman, Martijn Schonewille & Sebastiaan K. Koekkoek

  2. Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences (KNAW), Amsterdam, 1105, BA, The Netherlands

    Chris I. De Zeeuw, Laurens W. J. Bosman & Laurens Witter

Authors
  1. Chris I. De Zeeuw
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Freek E. Hoebeek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurens W. J. Bosman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martijn Schonewille
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laurens Witter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sebastiaan K. Koekkoek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chris I. De Zeeuw.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Erasmus MC Department of Neuroscience homepage

Chris I. De Zeeuw's homepage

Glossary

Convergence ratio

The ratio of input cells versus output cells — for example, many Purkinje cells of the same microzone project to the same target neuron in the cerebellar nuclei, resulting in a high ratio.

Vestibulocerebellum

Part of the cerebellum (including the flocculus, nodulus and uvula) that controls compensatory eye and head movements.

Zone

A sagittal region of Purkinje cells in the cerebellar cortex that is up to 500 μm wide and that receives climbing fibres from a particular olivary subnucleus.

Microzone

A sagittal region of Purkinje cells within a cerebellar zone that is approximately 50 to 100 μm wide, that can be activated by a particular functional stimulus and that receives climbing fibres from a cluster of coupled olivary neurons.

Leakage current

Electrical current that is induced by synaptic afferents (for example, at olivary spines) that affects the efficiency of gap junction coupling between these spines.

Jitter

A measure for noise in spiking activities.

Patch

A group of Purkinje cells characterized by a common response to a particular mossy fibre input, and that covers a small irregular area rather than a parallel beam or sagittal zone.

Optokinetic reflex

Compensatory eye movements following visual whole-field stimulation.

Crus 2

Part of the cerebellar hemisphere immediately rostral to the paramedian lobule.

Paramedian lobule

Part of the cerebellar hemisphere immediately caudal to Crus 2.

CV2 value

Coefficient of variation for adjacent interspike intervals.

Downstate

The state of a cell in which the membrane potential is low and hardly any spikes are fired.

Upstate

The state of a cell in which the membrane potential is normal or high, and spikes are fired.

Rebound potentiation

Potentiation at the molecular layer interneuron–Purkinje cell synapse, which is facilitated by co-activition of the molecular layer interneuron and the climbing fibre innervating the same Purkinje cell.

Harmaline

A tremorgenic drug that induces oscillations in neurons of the inferior olive.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Zeeuw, C., Hoebeek, F., Bosman, L. et al. Spatiotemporal firing patterns in the cerebellum. Nat Rev Neurosci 12, 327–344 (2011). https://doi.org/10.1038/nrn3011

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3011

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing