PT  - JOURNAL ARTICLE
AU  - Fadi A. Issa
AU  - Christopher Mazzochi
AU  - Allan F. Mock
AU  - Diane M. Papazian
TI  - Spinocerebellar Ataxia Type 13 Mutant Potassium Channel Alters Neuronal Excitability and Causes Locomotor Deficits in Zebrafish
AID  - 10.1523/JNEUROSCI.6572-10.2011
DP  - 2011 May 04
TA  - The Journal of Neuroscience
PG  - 6831--6841
VI  - 31
IP  - 18
4099  - http://www.jneurosci.org/content/31/18/6831.short
4100  - http://www.jneurosci.org/content/31/18/6831.full
SO  - J. Neurosci.2011 May 04; 31
AB  - 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.