Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3

J Neurosci. 2011 Sep 7;31(36):13002-14. doi: 10.1523/JNEUROSCI.2789-11.2011.


The relationship between cerebellar dysfunction, motor symptoms, and neuronal loss in the inherited ataxias, including the polyglutamine disease spinocerebellar ataxia type 3 (SCA3), remains poorly understood. We demonstrate that before neurodegeneration, Purkinje neurons in a mouse model of SCA3 exhibit increased intrinsic excitability resulting in depolarization block and the loss of the ability to sustain spontaneous repetitive firing. These alterations in intrinsic firing are associated with increased inactivation of voltage-activated potassium currents. Administration of an activator of calcium-activated potassium channels, SKA-31, partially corrects abnormal Purkinje cell firing and improves motor function in SCA3 mice. Finally, expression of the disease protein, ataxin-3, in transfected cells increases the inactivation of Kv3.1 channels and shifts the activation of Kv1.2 channels to more depolarized potentials. Our results suggest that in SCA3, early Purkinje neuron dysfunction is associated with altered physiology of voltage-activated potassium channels. We further suggest that the observed changes in Purkinje neuron physiology contribute to disease pathogenesis, underlie at least some motor symptoms, and represent a promising therapeutic target in SCA3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzothiazoles
  • Blotting, Western
  • Cell Death / physiology
  • Cell Line
  • Cerebellum / physiopathology*
  • Elapid Venoms / pharmacology
  • Electrophysiological Phenomena
  • Humans
  • Immunohistochemistry
  • Machado-Joseph Disease / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Movement Disorders / physiopathology
  • Nerve Degeneration / pathology
  • Neural Conduction / physiology
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Peptides / physiology*
  • Potassium Channels, Calcium-Activated / physiology
  • Purkinje Cells / physiology
  • Shaker Superfamily of Potassium Channels / metabolism


  • Benzothiazoles
  • Elapid Venoms
  • Peptides
  • Potassium Channels, Calcium-Activated
  • Shaker Superfamily of Potassium Channels
  • naphtho(1,2-d)thiazol-2-ylamine
  • polyglutamine
  • dendrotoxin