Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo
- Geffen School of Medicine at UCLA, United States
- East Carolina University, United States
Abstract
Mutations in KCNC3, which encodes the Kv3.3 K+ channel, cause spinocerebellar ataxia 13 (SCA13). SCA13 exists in distinct forms with onset in infancy or adulthood. Using zebrafish, we tested the hypothesis that infant- and adult-onset mutations differentially affect the excitability and viability of Purkinje cells in vivo during cerebellar development. An infant-onset mutation dramatically and transiently increased Purkinje cell excitability, stunted process extension, impaired dendritic branching and synaptogenesis, and caused rapid cell death during cerebellar development. Reducing excitability increased early Purkinje cell survival. In contrast, an adult-onset mutation did not significantly alter basal tonic firing in Purkinje cells, but reduced excitability during evoked high frequency spiking. Purkinje cells expressing the adult-onset mutation matured normally and did not degenerate during cerebellar development. Our results suggest that differential changes in the excitability of cerebellar neurons contribute to the distinct ages of onset and timing of cerebellar degeneration in infant- and adult-onset SCA13.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institutes of Health (R01 NS058500)
- Diane M Papazian
National Ataxia Foundation (NA)
- Fadi A Issa
UCLA Stein Oppenheimer Seed Grant (NA)
- Diane M Papazian
UCLA Jennifer Buchwald Graduate Fellowship (NA)
- Jui-Yi Hsieh
- Brittany N Ulrich
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of California, Los Angeles. The protocols were approved by the Chancellor's Animal Research Committee (#2005-176 and #1991-329). All surgery was performed under MS-222 anesthesia, and every effort was made to minimize suffering.
Copyright
© 2020, Hsieh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo
eLife 9:e57358.
https://doi.org/10.7554/eLife.57358
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