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

Vikram G. Shakkottai, Maria do Carmo Costa, James M. Dell'Orco, Ananthakrishnan Sankaranarayanan, Heike Wulff, Henry L. Paulson

Research output: Contribution to journalArticle

114 Scopus citations


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 voltageactivated potassium currents. Administration of an activator of calcium-activated potassium channels, SKA-31, partially corrects abnormal Purkinje cell firing and improves motor function inSCA3mice. 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.

Original languageEnglish (US)
Pages (from-to)13002-13014
Number of pages13
JournalJournal of Neuroscience
Issue number36
StatePublished - Sep 7 2011
Externally publishedYes


ASJC Scopus subject areas

  • Neuroscience(all)

Cite this