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

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

Research output: Contribution to journalArticle

264 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)389-397
Number of pages9
JournalNature Neuroscience
Volume9
Issue number3
DOIs
StatePublished - Mar 2006

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Cerebellar Diseases
Cerebellar Ataxia
Purkinje Cells
Calcium-Activated Potassium Channels
Ataxia
Calcium Channels
Synaptic Transmission
Synapses
Cerebellum
Neurotransmitter Agents
Perfusion
Mutation
Type 2 Episodic Ataxia
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. / Walter, Joy T.; Alviña, Karina; Womack, Mary D.; Chevez, Carolyn; Khodakhah, Kamran.

In: Nature Neuroscience, Vol. 9, No. 3, 03.2006, p. 389-397.

Research output: Contribution to journalArticle

Walter, Joy T. ; Alviña, Karina ; Womack, Mary D. ; Chevez, Carolyn ; Khodakhah, Kamran. / Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. In: Nature Neuroscience. 2006 ; Vol. 9, No. 3. pp. 389-397.
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