title: Disruption of metabotropic glutamate receptor signalling is a major defect at cerebellar parallel fibre-Purkinje cell synapses in staggerer mutant mice.
abstract: 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.
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mitsumura
authors.forename: Nobutake
authors.initials: N
authors.lastname: Hosoi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Furuya
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics*; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008818:Mice, Neurologic Mutants; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000235:genetics* / Q000473:pathology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1