Cbln1 is essential for synaptic integrity and plasticity in the cerebellum

Hirai, Hirokazu; Pang, Zhen; Bao, Dashi; Miyazaki, Toru; Li, Leyi; Miura, Eriko; Parris, Jennifer; Rong, Yongqi; Watanabe, Masahiko; Yuzaki, Michisuke; Morgan, James I.

doi:10.1038/nn1576

Cited by 298 publications

(417 citation statements)

References 33 publications

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“…These ectopic climbing fibre synapses appear around P10 when parallel fibre synapse formation and Purkinje cell dendritic arborization occur most vigorously. A similar type of multiple climbing fibre innervation was also found in a mutant mouse deficient in cerebellin in which parallel fibre to Purkinje cell synapse formation is severely impaired (Hirai et al 2005). These results suggest that parallel fibres compete with climbing fibres for the innervation territory during development and play a role in restricting climbing fibre innervation to proximal dendrites.…”

Section: Synapse Eliminationsupporting

confidence: 64%

Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

Kano

Hashimoto

Tabata

2008

Phil. Trans. R. Soc. B

103

110

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The cerebellum is a brain structure involved in the coordination, control and learning of movements, and elucidation of its function is an important issue. Japanese scholars have made seminal contributions in this field of neuroscience. Electrophysiological studies of the cerebellum have a long history in Japan since the pioneering works by Ito and Sasaki. Elucidation of the basic circuit diagram of the cerebellum in the 1960s was followed by the construction of cerebellar network theories and finding of their neural correlates in the 1970s. A theoretically predicted synaptic plasticity, long-term depression (LTD) at parallel fibre to Purkinje cell synapse, was demonstrated experimentally in 1982 by Ito and co-workers. Since then, Japanese neuroscientists from various disciplines participated in this field and have made major contributions to elucidate molecular mechanisms underlying LTD. An important pathway for LTD induction is type-1 metabotropic glutamate receptor (mGluR1) and its downstream signal transduction in Purkinje cells. Sugiyama and co-workers demonstrated the presence of mGluRs and Nakanishi and his pupils identified the molecular structures and functions of the mGluR family. Moreover, the authors contributed to the discovery and elucidation of several novel functions of mGluR1 in cerebellar Purkinje cells. mGluR1 turned out to be crucial for the release of endocannabinoid from Purkinje cells and the resultant retrograde suppression of transmitter release. It was also found that mGluR1 and its downstream signal transduction in Purkinje cells are indispensable for the elimination of redundant synapses during post-natal cerebellar development. This article overviews the seminal works by Japanese neuroscientists, focusing on mGluR1 signalling in cerebellar Purkinje cells.

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Section: Synapse Eliminationsupporting

confidence: 64%

Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

Kano

Hashimoto

Tabata

2008

Phil. Trans. R. Soc. B

103

110

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“…However, it is also possible that ␦2 or ␦1 influences GN axons indirectly through extracellular or postsynaptic molecules. The involvement of secreted molecules in synapse formation has been reported (2,25,26). It is also known that GluR2, an AMPA-type iGluR subunit, interacts with a cell adhesion molecule, N-cadherin, on the postsynaptic membrane (27).…”

Section: Discussionmentioning

confidence: 99%

Postsynaptic glutamate receptor δ family contributes to presynaptic terminal differentiation and establishment of synaptic transmission

Kuroyanagi

Yokoyama

Hirano

2009

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic adhesion molecules such as neuroligin are involved in synapse formation, whereas ionotropic transmitter receptors mediate fast synaptic transmission. In mutant mice deficient in the glutamate receptor ␦2 subunit (␦2), the number of synapses between granule neurons (GNs) and a Purkinje neuron (PN) in the cerebellum is reduced. Here, we have examined the role of ␦2 in synapse formation using culture preparations. First, we found that the size and number of GN presynaptic terminals on a PN in the primary culture prepared from knockout mice were smaller than those in control culture. Next we expressed ␦2 in nonneuronal human embryonic kidney (HEK) cells and cocultured them with GNs. Punctate structures expressing marker proteins for glutamatergic presynaptic terminals were accumulated around the HEK cells. Furthermore, HEK cells expressing both ␦2 and GluR1, a glutamate receptor subunit forming a functional glutamate-gated ion channel, showed postsynaptic current. Deletion of the extracellular leucine/isoleucine/valine binding protein (LIVBP) domain of ␦2 abolished the induction ability, and the LIVBP domain directly fused to a transmembrane sequence was sufficient to induce presynaptic differentiation. Furthermore, a mutant GluR1 whose LIVBP domain was replaced with the ␦2 LIVBP domain was sufficient by itself to establish synaptic transmission. Another member of ␦ glutamate receptor family ␦1 also induced presynaptic differentiation. Thus, the ␦ glutamate receptor subfamily can induce the differentiation of glutamatergic presynaptic terminals and contribute to the establishment of synaptic transmission.cerebellum ͉ granule neuron ͉ Purkinje neuron ͉ synapse formation S ynapse formation requires the accumulation and organization of multiple proteins on both the pre-and postsynaptic sides (1, 2). Previous studies have shown that expression of postsynaptic neuroligin in a nonneuronal cell triggers presynaptic differentiation in a contacting axon through interaction with presynaptic neurexin (3, 4). The involvement of other synaptic adhesion proteins, such as SynCAM and cadherin, in the formation or maintenance of synaptic structures has also been reported (5-7). For synaptic function, the most important postsynaptic proteins are receptors for neurotransmitters. Glutamate is the most prevalent neurotransmitter in the central nervous system, and there are ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors on the postsynaptic membrane. iGluR opens its pore domain to allow the permeation of cations when bound by glutamate, and mediates fast excitatory synaptic transmission (8, 9).So far, iGluR has not been shown to be directly related to synapse formation. However, in mutant mice deficient in the glutamate receptor ␦2 subunit (␦2), the number of synapses between granule neurons (GNs) and a Purkinje neuron (PN) is reduced, suggesting the involvement of ␦2 in synapse formation or maintenance (10, 11). ␦2 is selectively expressed in cerebellar PNs and has been classified as a member of the...

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“…7). Intriguingly, we have previously observed that Cbln1, which selectively interacts with the extracellular N-terminal domain of GluR␦2 to regulate the connectivity of PF-PC synapses (Hirai et al, 2005;Ito-Ishida et al, 2008;Matsuda et al, 2010;Uemura et al, 2010), is also localized in the synaptic cleft at PF-interneuron synapses (Miura et al, 2009). When subtracting the background labeling, labeling density for Cbln1 at PF-interneuron synapses also amounts to onefourth of that at PF-PC synapses [Miura et al (2009), their Fig.…”

Section: Glur␦2 Also Restricts the Number Of Ampars At Pf Synapses Inmentioning

confidence: 94%

Glutamate Receptor δ2 Is Essential for Input Pathway-Dependent Regulation of Synaptic AMPAR Contents in Cerebellar Purkinje Cells

Yamasaki¹,

Miyazaki²,

Azechi³

et al. 2011

J. Neurosci.

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The number of synaptic AMPA receptors (AMPARs) is the major determinant of synaptic strength and is differently regulated in input pathway-dependent and target cell type-dependent manners. In cerebellar Purkinje cells (PCs), the density of synaptic AMPARs is approximately five times lower at parallel fiber (PF) synapses than at climbing fiber (CF) synapses. However, molecular mechanisms underlying this biased synaptic distribution remain unclear. As a candidate molecule, we focused on glutamate receptor ␦2 (GluR␦2 or GluD2), which is known to be efficiently trafficked to and selectively expressed at PF synapses in PCs. We applied postembedding immunogold electron microscopy to GluR␦2 knock-out (KO) and control mice, and measured labeling density for GluA1-4 at three excitatory synapses in the cerebellar molecular layer. In both control and GluR␦2-KO mice, GluA1-3 were localized at PF and CF synapses in PCs, while GluA2-4 were at PF synapses in interneurons. In control mice, labeling density for each of GluA1-3 was four to six times lower at PF-PC synapses than at CF-PC synapses. In GluR␦2-KO mice, however, their labeling density displayed a three-to fivefold increase at PF synapses, but not at CF synapses, thus effectively eliminating input pathway-dependent disparity between the two PC synapses. Furthermore, we found an unexpected twofold increase in labeling density for GluA2 and GluA3, but not GluA4, at PF-interneuron synapses, where we identified low but significant expression of GluR␦2. These results suggest that GluR␦2 is involved in a common mechanism that restricts the number of synaptic AMPARs at PF synapses in PCs and molecular layer interneurons.

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Cbln1 is essential for synaptic integrity and plasticity in the cerebellum

Cited by 298 publications

References 33 publications

Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

Postsynaptic glutamate receptor δ family contributes to presynaptic terminal differentiation and establishment of synaptic transmission

Glutamate Receptor δ2 Is Essential for Input Pathway-Dependent Regulation of Synaptic AMPAR Contents in Cerebellar Purkinje Cells

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