The Cerebellum

, Volume 13, Issue 1, pp 29–41 | Cite as

Mutant Ataxin-3 with an Abnormally Expanded Polyglutamine Chain Disrupts Dendritic Development and Metabotropic Glutamate Receptor Signaling in Mouse Cerebellar Purkinje Cells

  • Ayumu Konno
  • Anton N. Shuvaev
  • Noriko Miyake
  • Koichi Miyake
  • Akira Iizuka
  • Serina Matsuura
  • Fathul Huda
  • Kazuhiro Nakamura
  • Shigeru Yanagi
  • Takashi Shimada
  • Hirokazu HiraiEmail author
Original Paper


Spinocerebellar ataxia type 3 (SCA3) is caused by the abnormal expansion of CAG repeats within the ataxin-3 gene. Previously, we generated transgenic mice (SCA3 mice) that express a truncated form of ataxin-3 containing abnormally expanded CAG repeats specifically in cerebellar Purkinje cells (PCs). Here, we further characterize these SCA3 mice. Whole-cell patch-clamp analysis of PCs from advanced-stage SCA3 mice revealed a significant decrease in membrane capacitance due to poor dendritic arborization and the complete absence of metabotropic glutamate receptor subtype1 (mGluR1)-mediated retrograde suppression of synaptic transmission at parallel fiber terminals, with an overall preservation of AMPA receptor-mediated fast synaptic transmission. Because these cerebellar phenotypes are reminiscent of retinoic acid receptor-related orphan receptor α (RORα)-defective staggerer mice, we examined the levels of RORα in the SCA3 mouse cerebellum by immunohistochemistry and found a marked reduction of RORα in the nuclei of SCA3 mouse PCs. To confirm that the defects in SCA3 mice were caused by postnatal deposition of mutant ataxin-3 in PCs, not by genome disruption via transgene insertion, we tried to reduce the accumulation of mutant ataxin-3 in developing PCs by viral vector-mediated expression of CRAG, a molecule that facilitates the degradation of stress proteins. Concomitant with the removal of mutant ataxin-3, CRAG-expressing PCs had greater numbers of differentiated dendrites compared to non-transduced PCs and exhibited retrograde suppression of synaptic transmission following mGluR1 activation. These results suggest that postnatal nuclear accumulation of mutant ataxin-3 disrupts dendritic differentiation and mGluR-signaling in SCA3 mouse PCs, and this disruption may be caused by a defect in a RORα-driven transcription pathway.


Purkinje cell Metabotropic glutamate receptor Endocannabinoid Spinocerebellar ataxia type 3 Patch clamp 



The authors are very grateful to Noriyuki Koibuchi for providing us with staggerer mutant mice. The authors would like to thank Dr. Andrey N. Shuvaev from the Institute of Undergraduate Core Programs, Siberian Federal University for his advice on our statistical analysis. This work was supported in part by the Funding Program for Next Generation World-Leading Researchers (LS021) to H. H and JSPS KAKENHI grant number 24700394 to A. K.

Conflict of Interest

All authors state that there are no actual or potential conflicts of interest concerning the work presented in this manuscript.

Supplementary material

12311_2013_516_MOESM1_ESM.pdf (1.1 mb)
ESM 1 (PDF 1112 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ayumu Konno
    • 1
  • Anton N. Shuvaev
    • 1
    • 2
  • Noriko Miyake
    • 3
  • Koichi Miyake
    • 3
  • Akira Iizuka
    • 1
  • Serina Matsuura
    • 1
  • Fathul Huda
    • 1
  • Kazuhiro Nakamura
    • 1
  • Shigeru Yanagi
    • 4
  • Takashi Shimada
    • 3
  • Hirokazu Hirai
    • 1
    Email author
  1. 1.Department of NeurophysiologyGunma University Graduate School of MedicineMaebashiJapan
  2. 2.Department of Neurosurgery and NeurologyKrasnoyarsk State Medical UniversityKrasnoyarskRussia
  3. 3.Department of Biochemistry and Molecular BiologyNippon Medical SchoolTokyoJapan
  4. 4.Laboratory of Molecular Biochemistry, Graduate School of Life SciencesTokyo University of Pharmacy and Life SciencesTokyoJapan

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