Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2

James M. Dell'Orco, Stefan M. Pulst, Vikram G. Shakkottai

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Alterations in Purkinje neuron firing often accompany ataxia, but the molecular basis for these changes is poorly understood. In a mouse model of spinocerebellar ataxia type 2 (SCA2), a progressive reduction in Purkinje neuron firing frequency accompanies cell atrophy. We investigated the basis for altered Purkinje neuron firing in SCA2. A reduction in the expression of large-conductance calcium-activated potassium (BK) channels and Kv3.3 voltage-gated potassium channels accompanies the inability of Purkinje neurons early in disease to maintain repetitive spiking. In association with prominent Purkinje neuron atrophy, repetitive spiking is restored, although at a greatly reduced firing frequency. In spite of a continued impairment in spike repolarization and a persistently reduced BK channel mediated afterhyperpolarization (AHP), repetitive spiking is maintained, through the increased activity of barium-sensitive potassium channels, most consistent with inwardly rectifying potassium(Kir) channels. Increased activity of Kir channels results in the generation of a novel AHP not seen in wild-type Purkinje neurons that also accounts for the reduced firing frequency late in disease. Homeostatic changes in Purkinje neuron morphology that help to preserve repetitive spiking can also therefore have deleterious consequences for spike frequency. These results suggest that the basis for spiking abnormalities in SCA2 differ depending on disease stage, and interventions targeted towards correcting potassium channel dysfunction in ataxia need to be tailored to the specific stage in the degenerative process.

Original languageEnglish (US)
Pages (from-to)3935-3945
Number of pages11
JournalHuman molecular genetics
Issue number20
StatePublished - Oct 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Potassium channel dysfunction underlies Purkinje neuron spiking abnormalities in spinocerebellar ataxia type 2'. Together they form a unique fingerprint.

Cite this