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

Jui-Yi Hsieh,Brittany N Ulrich,Meng-Chin A Lin,Fadi A Issa,Diane M Papazian,Brandon Brown

doi:10.7554/elife.57358

Jui-Yi Hsieh, Brittany N Ulrich + Show 4 more

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https://doi.org/10.7554/elife.57358

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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.

Highlights

Spinocerebellar ataxias (SCAs) are a group of rare, autosomal dominant diseases characterized by locomotor deficits and cerebellar degeneration, typically with onset in adulthood (Klockgether et al, 2019)
We propose that the defective maturation and highly penetrant death of iR4H-expressing Purkinje cells in zebrafish during cerebellar development are mechanistically related to the cerebellar maldevelopment, atrophy, and degeneration that occurs during infancy in patients with early-onset Spinocerebellar ataxia 13 (SCA13)
To test the hypothesis that infant- and adult-onset SCA13 mutations alter Purkinje cell excitability in distinct ways, the aR3H or iR4H mutant subunits or exogenous wild-type Kv3.3 subunits were expressed in the zebrafish cerebellum under the control of the Purkinje cell-specific aldoca promoter using F0 transgenesis, which results in a mosaic pattern of expression (Kikuta and Kawakami, 2009; Tanabe et al, 2010)

Summary

Introduction

Spinocerebellar ataxias (SCAs) are a group of rare, autosomal dominant diseases characterized by locomotor deficits and cerebellar degeneration, typically with onset in adulthood (Klockgether et al, 2019). The infant- and adult-onset forms of SCA13 are caused by distinct mutations in Kv3.3 (Waters et al, 2006; Figueroa et al, 2010; Figueroa et al, 2011; Duarri et al, 2015). The age of onset is strongly correlated with the same mutation in unrelated families, indicating that the two forms of

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