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Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia

Nature Neuroscience volume 9, pages 389–397 (2006)Cite this article

Abstract

Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (KCa) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that KCa channels may constitute a potential therapeutic target in EA2.

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Figure 1: Intrinsic pacemaking in leaner and ducky mutant mice is highly irregular.
Figure 2: Partial pharmacological blockade of P/Q-type voltage-gated calcium channels reduces the precision of intrinsic pacemaking in Purkinje cells.
Figure 3: The activity of mutant ducky Purkinje cells less accurately encodes the strength and timing of its synaptic input.
Figure 4: Activation of SK channels with EBIO recovers the precision of intrinsic pacemaking in Purkinje cells by increasing the AHP.
Figure 5: P/Q channel mutations affect the precision of pacemaking in the presence of inhibitory synaptic transmission.
Figure 6: Chronic in vivo activation of cerebellar SK channels improves motor performance in ducky mice.
Figure 7: Chronic perfusion of EBIO does not affect the motor performance of C57BL or CD1 mice.
Figure 8: EBIO reduces the severity and the frequency of dyskinesia and improves motor performance in tottering mice.

References

  1. Ito, M. The Cerebellum and Neural Control (Raven, New York, 1984).

    Google Scholar 

  2. 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  Google Scholar 

  3. 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 

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

    Article  CAS  Google Scholar 

  5. Nam, S.C. & Hockberger, P.E. Analysis of spontaneous electrical activity in cerebellar Purkinje cells acutely isolated from postnatal rats. J. Neurobiol. 33, 18–32 (1997).

    Article  CAS  Google Scholar 

  6. Womack, M. & Khodakhah, K. Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons. J. Neurosci. 22, 10603–10612 (2002).

    Article  CAS  Google Scholar 

  7. Armstrong, D.M. & Rawson, J.A. Activity patterns of cerebellar cortical neurones and climbing fibre afferents in the awake cat. J. Physiol. (Lond.) 289, 425–448 (1979).

    Article  CAS  Google Scholar 

  8. Eccles, J.C., Llinas, R. & Sasaki, K. Intracellularly recorded responses of the cerebellar Purkinje cells. Exp. Brain Res. 1, 161–183 (1966).

    CAS  Google Scholar 

  9. Eccles, J.C., Sasaki, K. & Strata, P. A comparison of the inhibitory actions of Golgi cells and of basket cells. Exp. Brain Res. 3, 81–94 (1967).

    CAS  Google Scholar 

  10. Granit, R. & Phillips, C.G. Excitatory and inhibitory processes acting upon individual Purkinje cells of the cerebellum in cats. J. Physiol. (Lond.) 133, 520–547 (1956).

    Article  CAS  Google Scholar 

  11. Jaeger, D. & Bower, J.M. Prolonged responses in rat cerebellar Purkinje cells following activation of the granule cell layer: an intracellular in vitro and in vivo investigation. Exp. Brain Res. 100, 200–214 (1994).

    Article  CAS  Google Scholar 

  12. 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  Google Scholar 

  13. Womack, M.D., Chevez, C. & Khodakhah, K. Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons. J. Neurosci. 24, 8818–8822 (2004).

    Article  CAS  Google Scholar 

  14. Womack, M.D. & Khodakhah, K. Characterization of large conductance Ca2+-activated K+ channels in cerebellar Purkinje neurons. Eur. J. Neurosci. 16, 1214–1222 (2002).

    Article  Google Scholar 

  15. Edgerton, J.R. & Reinhart, P.H. Distinct contributions of small and large conductance Ca2+-activated K+ channels to rat Purkinje neuron function. J. Physiol. (Lond.) 548, 53–69 (2003).

    Article  CAS  Google Scholar 

  16. Cingolani, L.A., Gymnopoulos, M., Boccaccio, A., Stocker, M. & Pedarzani, P. Developmental regulation of small-conductance Ca2+-activated K+ channel expression and function in rat Purkinje neurons. J. Neurosci. 22, 4456–4467 (2002).

    Article  CAS  Google Scholar 

  17. Swensen, A.M. & Bean, B.P. Ionic mechanisms of burst firing in dissociated Purkinje neurons. J. Neurosci. 23, 9650–9663 (2003).

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Shakkottai, V.G. et al. Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J. Clin. Invest. 113, 582–590 (2004).

    Article  CAS  Google Scholar 

  20. Doyle, J.L. & Stubbs, L. Ataxia, arrhythmia and ion-channel gene defects. Trends Genet. 14, 92–98 (1998).

    Article  CAS  Google Scholar 

  21. Pietrobon, D. Calcium channels and channelopathies of the central nervous system. Mol. Neurobiol. 25, 31–50 (2002).

    Article  CAS  Google Scholar 

  22. Dunlap, K., Luebke, J.I. & Turner, T.J. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18, 89–98 (1995).

    Article  CAS  Google Scholar 

  23. Fletcher, C.F. et al. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J. 15, 1288–1290 (2001).

    Article  CAS  Google Scholar 

  24. Barclay, J. et al. Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J. Neurosci. 21, 6095–6104 (2001).

    Article  CAS  Google Scholar 

  25. Dove, L.S., Abbott, L.C. & Griffith, W.H. Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. J. Neurosci. 18, 7687–7699 (1998).

    Article  CAS  Google Scholar 

  26. Lorenzon, N.M., Lutz, C.M., Frankel, W.N. & Beam, K.G. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. J. Neurosci. 18, 4482–4489 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Brodbeck, J. et al. The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function. J. Biol. Chem. 277, 7684–7693 (2002).

    Article  CAS  Google Scholar 

  29. 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  Google Scholar 

  30. Pedarzani, P. et al. Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J. Biol. Chem. 276, 9762–9769 (2001).

    Article  CAS  Google Scholar 

  31. Carter, A.G. & Regehr, W.G. Quantal events shape cerebellar interneuron firing. Nat. Neurosci. 5, 1309–1318 (2002).

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  34. Wakamori, M. et al. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel. J. Biol. Chem. 273, 34857–34867 (1998).

    Article  CAS  Google Scholar 

  35. Eccles, J.C. The cerebellum as a computer: patterns in space and time. J. Physiol. (Lond.) 229, 1–32 (1973).

    Article  CAS  Google Scholar 

  36. Gancher, S.T. & Nutt, J.G. Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov. Disord. 1, 239–253 (1986).

    Article  CAS  Google Scholar 

  37. Griggs, R.C. & Nutt, J.G. Episodic ataxias as channelopathies. Ann. Neurol. 37, 285–287 (1995).

    Article  CAS  Google Scholar 

  38. Harno, H. et al. Acetazolamide improves neurotological abnormalities in a family with episodic ataxia type 2 (EA-2). J. Neurol. 251, 232–234 (2004).

    Article  Google Scholar 

  39. Herson, P.S. et al. A mouse model of episodic ataxia type-1. Nat. Neurosci. 6, 378–383 (2003).

    Article  CAS  Google Scholar 

  40. Kaunisto, M.A. et al. Novel splice site CACNA1A mutation causing episodic ataxia type 2. Neurogenetics 5, 69–73 (2004).

    Article  CAS  Google Scholar 

  41. Tricarico, D., Barbieri, M., Mele, A., Carbonara, G. & Camerino, D.C. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J. 18, 760–761 (2004).

    Article  CAS  Google Scholar 

  42. Tricarico, D., Barbieri, M. & Camerino, D.C. Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann. Neurol. 48, 304–312 (2000).

    Article  CAS  Google Scholar 

  43. 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  Google Scholar 

  44. Jun, K. et al. Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)- subunit. Proc. Natl. Acad. Sci. USA 96, 15245–15250 (1999).

    Article  CAS  Google Scholar 

  45. Piedras-Renteria, E.S. et al. Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca2+ entry pathway. Proc. Natl. Acad. Sci. USA 101, 3609–3614 (2004).

    Article  CAS  Google Scholar 

  46. Khavandgar, S., Walter, J.T., Sageser, K. & Khodakhah, K. Kv1 channels selectively prevent dendritic hyperexcitability in rat Purkinje cells. J. Physiol. (Lond.) 569, 545–557 (2005).

    Article  CAS  Google Scholar 

  47. Womack, M.D. & Khodakhah, K. Dendritic control of spontaneous bursting in cerebellar Purkinje cells. J. Neurosci. 24, 3511–3521 (2004).

    Article  CAS  Google Scholar 

  48. Stone, T.W. Neuropharmacology of quinolinic and kynurenic acids. Pharmacol. Rev. 45, 309–379 (1993).

    CAS  Google Scholar 

  49. Yoon, K.W., Covey, D.F. & Rothman, S.M. Multiple mechanisms of picrotoxin block of GABA-induced currents in rat hippocampal neurons. J. Physiol. (Lond.) 464, 423–439 (1993).

    Article  CAS  Google Scholar 

  50. Weisz, C.J., Raike, R.S., Soria-Jasso, L.E. & Hess, E.J. Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering. J. Neurosci. 25, 4141–4145 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the New York City Council Speaker's Fund for Biomedical Research and by the US National Institutes of Health.

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  1. Department of Neuroscience, Albert Einstein College of Medicine, 506 Kennedy Center, 1410 Pelham Parkway South, Bronx, 10461, New York, USA

    Joy T Walter, Karina Alviña, Mary D Womack, Carolyn Chevez & Kamran Khodakhah

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Correspondence to Kamran Khodakhah.

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Supplementary information

Supplementary Fig. 1

The efficacy of parallel fibre (PF) to Purkinje cell synaptic transmission is not affected in the ducky mice. (PDF 87 kb)

Supplementary Fig. 2

Simulation of spontaneous and PF-evoked synaptic inputs in wild type and mutant mice. (PDF 78 kb)

Supplementary Video (WMV 2772 kb)

Supplementary Methods (PDF 45 kb)

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Walter, J., Alviña, K., Womack, M. et al. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci 9, 389–397 (2006). https://doi.org/10.1038/nn1648

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