| First Author | Mitsumura K | Year | 2011 |
| Journal | J Physiol | Volume | 589 |
| Issue | Pt 13 | Pages | 3191-209 |
| PubMed ID | 21558162 | Mgi Jnum | J:189405 |
| Mgi Id | MGI:5445481 | Doi | 10.1113/jphysiol.2011.207563 |
| Citation | Mitsumura K, et al. (2011) Disruption of metabotropic glutamate receptor signalling is a major defect at cerebellar parallel fibre-Purkinje cell synapses in staggerer mutant mice. J Physiol 589(Pt 13):3191-209 |
| abstractText | Staggerer mutant mice have functional loss of a transcription factor, retinoid-related orphan receptor alpha (RORalpha), 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 RORalpha 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 ( approximately 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. |
