Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo

• Published in: eLife 2020-07, Vol.9
• Main Authors: Hsieh, Jui-Yi, Ulrich, Brittany N, Issa, Fadi A, Lin, Meng-Chin A, Brown, Brandon, Papazian, Diane M
• Format: Article
• Language: English
• Subjects: Age; Age Factors; Animals; Ataxia; Cell death; Cell survival; Cell Survival - genetics; cerebellar development; Cerebellum; Cerebellum - growth & development; Degeneration; Dendritic branching; Disease Models, Animal; Excitability; Genetic aspects; Machado-Joseph disease; Maturation; Mutation; Neuroscience; Potassium channels (voltage-gated); Purkinje cell; Purkinje cells; Purkinje Cells - physiology; Shaw Potassium Channels - genetics; spinocerebellar ataxia; Spinocerebellar Ataxias - congenital; Spinocerebellar Ataxias - genetics; Synaptogenesis; Zebrafish; Zebrafish Proteins - genetics
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.57358

Mutations in , 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.