Formation and maturation of parallel fiber‐purkinje cell synapses in the <i>staggerer</i> cerebellum ex vivo

Janmaat, Sonja; Frédéric, Florence; Sjollema, Klaas; Luiten, P.G.M.; Mariani, Jean; Want, J.J.L. van der

doi:10.1002/cne.21910

Cited by 7 publications

(11 citation statements)

References 65 publications

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“…It has been reported that PFs in sg / sg mice are able to establish a small number of immature junctional complexes onto PC dendrites morphologically, although those synaptic contacts scarcely develop into spine‐shaped mature synapses (Hirano & Dembitzer, 1975; Sotelo, 1975, 1990; Landis & Reese, 1977; Berry et al 1978; Janmaat et al 2009). To assess the functional properties of such PF–PC synapses in staggerer mutant mice, we tried to record PF‐evoked excitatory synaptic responses from voltage‐clamped PCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The surviving PCs (∼20%) (Herrup & Mullen, 1981; Doulazmi et al 2001) can form synapses with climbing fibres, although they remain multiply innervated even at adult age because of a failure in the developmental elimination of surplus climbing fibres (Mariani & Changeux, 1980; Steinmayr et al 1998). On the other hand, it has been reported that parallel fibres (PFs) cannot make mature spine‐type functional synapses onto PCs in sg / sg mice (Hirano & Dembitzer, 1975; Sotelo, 1975, 1990; Landis & Reese, 1977; Berry et al 1978; Janmaat et al 2009); however, previous ultrastructural studies also showed that some PFs from remaining granule cells are able to form primitive synapse‐like junctional structures on sg / sg PCs (Sotelo, 1973, 1975, 1990; Hirano & Dembitzer, 1975; Berry et al 1978). It remains unclear whether such primitive junctions function as synapses since detailed electrophysiological investigation has not been performed on PF–PC synaptic transmission in sg / sg mice.…”

Section: Introductionmentioning

confidence: 99%

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

Mitsumura¹,

Hosoi²,

Furuya³

et al. 2011

The Journal of Physiology

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Non-technical summary Homozygous staggerer mutant (sg/sg) mice exhibit cerebellar atrophy and congenital ataxia, and serve as an important extreme mouse model of the hereditary spinocerebellar ataxia type 1 (SCA1), since the staggerer mutation is closely related to SCA1 pathology. However, we know little about synaptic abnormalities at cerebellar parallel fibre (PF)-Purkinje cell (PC) synapses in sg/sg mice, which could underlie SCA1 pathology. In this study, we report that PFs still make reasonably functional fast synapses onto PCs in sg/sg mice despite reduction in the number of PF-PC synapses. In contrast, sg/sg mice lack metabotropic glutamate receptor (mGluR)-mediated slow synaptic transmission completely. Synaptic modulation caused by mGluR-mediated endocannabinoid release is also abolished at sg/sg PF-PC synapses. Our results indicate that major synaptic abnormality is disruption of cerebellar mGluR signalling in SCA1-related sg/sg mice, and that mGluR signalling can be one of the key factors to SCA1 pathology.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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mitsumura¹,

Hosoi²,

Furuya³

et al. 2011

The Journal of Physiology

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“…cells (Gö rcs et al, 1993;Hà mori et al, 1996;Knö pfel and Grandes, 2002) were mGlu1a immunopositive. MGlu1 has also been localized in somata and dendrites of the cerebellar Staggerer mouse Purkinje cells in organotypic cultures (Janmaat et al, 2009). Furthermore, we have revealed the subcellular localization of mGlu1a receptor in the organotypic cultures using two different immunocytochemical techniques for electron microscopy.…”

Section: Discussionmentioning

confidence: 96%

“…Labelled with adequate immunohistochemical markers (Enderlin et al, 1987;Weiser et al, 1995;Sekirnjak et al, 1997;Liu and Kaczmarek, 1998;Diñ o et al, 1999;Shibata et al, 1999;Ló pez Bendito et al, 2001;Knö pfel and Grandes, 2002;Bastianelli, 2003;Sacco et al, 2006), cultured cerebellum renders a mixture of preserved (Janmaat et al, 2009) and altered features. Despite the lack of the extrinsic climbing and mossy fibres, the immunohistochemical characteristics and morphology of the granule and Golgi cells were maintained in our cultures.…”

Section: Discussionmentioning

confidence: 99%

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Conserved cellular distribution of the glutamate receptors GluA2/3, mGlu1a and mGlu2/3 in isolated cultures of rat cerebellum

Ramos-Uriarte

Elezgarai

Grandes

et al. 2012

Journal of Chemical Neuroanatomy

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Nuclear factor one X regulates the development of multiple cellular populations in the postnatal cerebellum

Piper

Harris

Barry

et al. 2011

J of Comparative Neurology

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Development of the cerebellum involves the coordinated proliferation, differentiation, maturation, and integration of cells from multiple neuronal and glial lineages. In rodent models, much of this occurs in the early postnatal period. However, our understanding of the molecular mechanisms that regulate this phase of cerebellar development remains incomplete. Here, we address the role of the transcription factor nuclear factor one X (NFIX), in postnatal development of the cerebellum. NFIX is expressed by progenitor cells within the external granular layer and by cerebellar granule neurons within the internal granule layer. Using NFIX−/− mice, we demonstrate that the development of cerebellar granule neurons and Purkinje cells within the postnatal cerebellum is delayed in the absence of this transcription factor. Furthermore, the differentiation of mature glia within the cerebellum, such as Bergmann glia, is also significantly delayed in the absence of NFIX. Collectively, the expression pattern of NFIX, coupled with the delays in the differentiation of multiple cell populations of the developing cerebellum in NFIX−/− mice, suggest a central role for NFIX in the regulation of cerebellar development, highlighting the importance of this gene for the maturation of this key structure.

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Formation and maturation of parallel fiber‐purkinje cell synapses in the staggerer cerebellum ex vivo

Cited by 7 publications

References 65 publications

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

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

Conserved cellular distribution of the glutamate receptors GluA2/3, mGlu1a and mGlu2/3 in isolated cultures of rat cerebellum

Nuclear factor one X regulates the development of multiple cellular populations in the postnatal cerebellum

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