PUBLICATION
Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish
- Authors
- Issa, F.A., Mazzochi, C., Mock, A.F., and Papazian, D.M.
- ID
- ZDB-PUB-110520-5
- Date
- 2011
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 31(18): 6831-6841 (Journal)
- Registered Authors
- Papazian, Diane M.
- Keywords
- none
- MeSH Terms
-
- Action Potentials/genetics
- Animals
- Animals, Genetically Modified
- Electrophysiology
- Humans
- Immunohistochemistry
- Motor Activity/genetics*
- Motor Neurons/physiology*
- Mutation*
- Shaw Potassium Channels/genetics*
- Shaw Potassium Channels/metabolism
- Spinocerebellar Ataxias/genetics*
- Zebrafish
- PubMed
- 21543613 Full text @ J. Neurosci.
Citation
Issa, F.A., Mazzochi, C., Mock, A.F., and Papazian, D.M. (2011) Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish. The Journal of neuroscience : the official journal of the Society for Neuroscience. 31(18):6831-6841.
Abstract
Whether changes in neuronal excitability can cause neurodegenerative disease in the absence of other factors such as protein
aggregation is unknown. Mutations in the Kv3.3 voltage-gated K+ channel cause spinocerebellar ataxia type 13 (SCA13), a human autosomal-dominant disease characterized by locomotor impairment
and the death of cerebellar neurons. Kv3.3 channels facilitate repetitive, high-frequency firing of action potentials, suggesting
that pathogenesis in SCA13 is triggered by changes in electrical activity in neurons. To investigate whether SCA13 mutations
alter excitability in vivo, we expressed the human dominant-negative R420H mutant subunit in zebrafish. The disease-causing mutation specifically suppressed
the excitability of Kv3.3-expressing, fast-spiking motor neurons during evoked firing and fictive swimming and, in parallel,
decreased the precision and amplitude of the startle response. The dominant-negative effect of the mutant subunit on K+ current amplitude was directly responsible for the reduced excitability and locomotor phenotype. Our data provide strong
evidence that changes in excitability initiate pathogenesis in SCA13 and establish zebrafish as an excellent model system
for investigating how changes in neuronal activity impair locomotor control and cause cell death.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping