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Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo
Jui-Yi Hsieh1,2, Brittany N Ulrich1,2, Fadi A Issa1
1Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, United States.
Insights
Infant-onset spinocerebellar ataxia 13 (SCA13) mutations rapidly kill developing neurons by increasing excitability. Adult-onset SCA13 mutations do not affect neuron survival, suggesting distinct disease mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Mutations in KCNC3, encoding the Kv3.3 K+ channel, cause spinocerebellar ataxia 13 (SCA13).
- SCA13 presents with distinct infant or adult onset forms.
- Purkinje cells are crucial for motor coordination and are affected in SCA13.
Purpose of the Study:
- To investigate how infant- and adult-onset KCNC3 mutations differentially impact Purkinje cell excitability and survival during cerebellar development.
- To test the hypothesis that distinct excitability changes underlie different SCA13 onset ages.
Main Methods:
- Utilized zebrafish as a model organism to study cerebellar development in vivo.
- Examined the effects of infant- and adult-onset KCNC3 mutations on Purkinje cell excitability, process extension, dendritic branching, synaptogenesis, and viability.
- Manipulated excitability to assess its role in Purkinje cell survival.
Main Results:
- An infant-onset mutation transiently increased Purkinje cell excitability, impaired development, and caused rapid cell death.
- Reducing excitability in early development improved Purkinje cell survival.
- An adult-onset mutation did not affect basal excitability or cause Purkinje cell degeneration during development.
Conclusions:
- Differential alterations in Purkinje cell excitability contribute to the distinct clinical presentations and timing of cerebellar degeneration in infant- versus adult-onset SCA13.
- Targeting excitability may offer therapeutic strategies for SCA13.
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.
