SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity

Seung Yun Yoo, Mark E. Pennesi, Edwin J. Weeber, Bisong Xu, Richard Atkinson, Shiming Chen, Dawna L. Armstrong, Samuel M. Wu, J. David Sweatt, Huda Y. Zoghbi

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Abstract

We targeted 266 CAG repeats (a number that causes infantile-onset disease) into the mouse Sca7 locus to generate an authentic model of spinocerebellar ataxia type 7 (SCA7). These mice reproduced features of infantile SCA7 (ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments. Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however, ataxin-7 staining became more pronounced. Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of nuclear inclusions. These data demonstrate that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).

Original languageEnglish (US)
Pages (from-to)383-401
Number of pages19
JournalNeuron
Volume37
Issue number3
DOIs
StatePublished - Feb 6 2003

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Yoo, S. Y., Pennesi, M. E., Weeber, E. J., Xu, B., Atkinson, R., Chen, S., Armstrong, D. L., Wu, S. M., Sweatt, J. D., & Zoghbi, H. Y. (2003). SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron, 37(3), 383-401. https://doi.org/10.1016/S0896-6273(02)01190-X