Disruption of metabotropic glutamate receptor signalling is a major defect at cerebellar parallel fibre-Purkinje cell synapses in staggerer mutant mice

J Physiol. 2011 Jul 1;589(Pt 13):3191-209. doi: 10.1113/jphysiol.2011.207563. Epub 2011 May 9.


Staggerer mutant mice have functional loss of a transcription factor, retinoid-related orphan receptor α (RORα), which is abundantly expressed in Purkinje cells (PCs) of the cerebellum.Homozygous staggerer (sg/sg)mice show cerebellar hypoplasia and congenital ataxia. Sg/sg mice serve as an important extreme mouse model of the hereditary spinocerebellar ataxia type 1 (SCA1), since it has been shown that RORα dysfunction is strongly correlated with SCA1 pathogenesis. However, synaptic abnormalities, especially at parallel fibre (PF)-PC synapses, in SCA1-related sg/sg mice have not been examined in detail electrophysiologically. In this study, we report that PFs can still establish functional synapses onto PCs in sg/sg mice in spite of reduction in the number of PF-PC synapses. Compared with PF-evoked EPSCs in the wild-type or heterozygotes, the success rate of the EPSC recordings in sg/sg was quite low (∼40%) and the EPSCs showed faster kinetics and slightly decreased paired pulse facilitation at short intervals. The prominent synaptic dysfunction is that sg/sg mice lack metabotropic glutamate receptor (mGluR)-mediated slow EPSCs completely. Neither intense PF stimulation nor an exogenously applied mGluR agonist, DHPG, could elicit mGluR-mediated responses.Western blot analysis in the sg/sg cerebellum revealed low-level expression of mGluR1 and TRPC3, both of which underlie mGluR-mediated slow currents in PCs. Immunohistochemical data demonstrated marked mislocalization of mGluR1 on sg/sg PCs.We found that mGluR-mediated retrograde suppression of PF-PC EPSCs by endocannabinoid is also impaired completely in sg/sg mice. These results suggest that disruption of mGluR signalling at PF-PC synapses is one of the major synaptic defects in sg/sg mice and may manifest itself in SCA1 pathology.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Excitatory Postsynaptic Potentials / genetics*
  • Homozygote
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Neurologic Mutants
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology*
  • Random Allocation
  • Receptors, Metabotropic Glutamate / deficiency*
  • Receptors, Metabotropic Glutamate / physiology
  • Signal Transduction / genetics*
  • Spinocerebellar Ataxias / genetics*
  • Spinocerebellar Ataxias / metabolism
  • Spinocerebellar Ataxias / pathology
  • Synapses / genetics*
  • Synapses / pathology


  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1