Control of Synaptic Connection by Glutamate Receptor δ2 in the Adult Cerebellum

Takeuchi, Tomonori; Miyazaki, Toru; Watanabe, Masahiko; Mori, Hisashi; Sakimura, Kenji; Mishina, Masayoshi

doi:10.1523/jneurosci.4740-04.2005

Cited by 113 publications

(143 citation statements)

References 54 publications

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“…There is clear evidence that postsynaptic GluR␦2 plays an essential role in vivo in the formation and maintenance of the PF-PC synapse in the cerebellum (Kashiwabuchi et al, 1995;Kurihara et al, 1997;Takeuchi et al, 2005). Recently, we revealed that GluR␦2 mediates PF-PC synapse formation in vivo by interacting with presynaptic NRXNs through Cbln1 (Uemura et al, 2010).…”

Section: Discussionmentioning

confidence: 95%

“…GluR␦2 is selectively expressed in cerebellar PCs (Araki et al, 1993;Lomeli et al, 1993) and is exclusively localized at PF-PC synapses (Takayama et al, 1996;Landsend et al, 1997). In conventional and conditional GluR␦2 knock-out mice, a significant number of PC spines lack synaptic contacts with PF terminals, and some of residual PF-PC synapses show mismatching between presynaptic and postsynaptic specializations (Kashiwabuchi et al, 1995;Kurihara et al, 1997;Takeuchi et al, 2005). These studies indicate that the formation and maintenance of PF-PC synapses are critically dependent on GluR␦2 in vivo.…”

Section: Introductionmentioning

confidence: 92%

“…GluR␦2, a member of the ␦-type glutamate receptor (GluR), plays an essential role in vivo in cerebellar Purkinje cell (PC) synapse formation (Kashiwabuchi et al, 1995;Kurihara et al, 1997;Takeuchi et al, 2005). The cerebellum receives two excitatory afferents, the climbing fiber and the mossy fiber-parallel fiber (PF) pathway, both converging onto PCs that are the sole neurons sending outputs from the cerebellar cortex.…”

Section: Introductionmentioning

confidence: 99%

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GluRδ2 Assembles Four Neurexins intoTrans-Synaptic Triad to Trigger Synapse Formation

Lee¹,

Uemura²,

Yoshida³

et al. 2012

J. Neurosci.

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Elucidation of molecular mechanisms of synapse formation is a prerequisite for the understanding of neural wiring, higher brain functions, and mental disorders. The trans-synaptic interaction of postsynaptic glutamate receptor ␦2 (GluR␦2) and presynaptic neurexins (NRXNs) through cerebellin precursor protein 1 (Cbln1) mediates synapse formation in vivo in the cerebellum. Here, we asked how the trans-synaptic triad induces synapse formation. Native GluR␦2 existed as a tetramer in the membrane, whereas the N-terminal domain (NTD) of GluR␦2 formed a stable homodimer. When incubated with cultured mouse cerebellar granule cells (GCs), dimeric GluR␦2-NTD and Cbln1 exerted little effect on the accumulation of punctate immunostaining signals for Bassoon and vesicular glutamate transporter 1 in GC axons. However, tetramerized GluR␦2-NTD stimulated the accumulation of these presynaptic proteins in the axons. Analysis of Cbln1 mutants suggested that the binding sites of GluR␦2 and NRXN1␤ on Cbln1 are differential. Furthermore, there was no competition in the binding to Cbln1 between GluR␦2-NTD and the extracellular domain (ECD) of NRXN1␤. Thus, GluR␦2 and Cbln1 interacted with each other rather independently of Cbln1-NRXN1␤ interaction and vice versa. Gel filtration and isothermal titration calorimetry analyses consistently showed that dimeric GluR␦2-NTD and hexameric Cbln1 assembled in the 1:1 ratio, whereas hexameric Cbln1 and the laminin-neurexin-sex hormone-binding globulin domain of NRXN1␤-ECD assembled in the 1:2 ratio. Thus, the synaptogenic triad is assembled from tetrameric GluR␦2, hexameric Cbln1, and monomeric NRXN in the ratio of 1:2:4. These results suggest that GluR␦2 triggers synapse formation by clustering four NRXNs through triad formation.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GluRδ2 Assembles Four Neurexins intoTrans-Synaptic Triad to Trigger Synapse Formation

Lee¹,

Uemura²,

Yoshida³

et al. 2012

J. Neurosci.

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show abstract

“…By the way, GluR␦2 also plays a role in stabilization of parallel fiber-PN synapse structure possibly through interaction with a molecule in the presynaptic active zone (Kurihara et al, 1997;Takeuchi et al, 2005;Hirano 2006). GluR␦2 is efficiently transported to plasma membrane and relatively evenly distributed in the postsynaptic density of parallel fiber-PN synapse.…”

Section: Discussionmentioning

confidence: 99%

Membrane-Proximal Region of Glutamate Receptor δ2 Subunit Is Critical for Long-Term Depression and Interaction with Protein Interacting with C Kinase 1 in a Cerebellar Purkinje Neuron

Yawata¹,

Tsuchida²,

Kengaku³

et al. 2006

J. Neurosci.

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The glutamate receptor ␦2 subunit (GluR␦2) is selectively expressed in cerebellar Purkinje neurons (PNs) and is involved in the long-term depression (LTD). However, little is known about the mechanism of its action. Acute expression of the wild-type GluR␦2 in the GluR␦2-deficient PN rescued the induction of LTD, suggesting the direct role of GluR␦2 in LTD. To identify the critical region of GluR␦2 necessary for LTD, we constructed and expressed various mutant GluR␦2 proteins in the GluR␦2-deficient PNs. The mutant GluR␦2 possessing the membrane-proximal 21 aa residues in the C-terminal cytoplasmic region rescued the induction of LTD, whereas the mutant with membrane-proximal 13 aa failed. In addition, overexpression of 865ϳ871 aa of GluR␦2 (corresponding to membrane-proximal 14 -20 aa) fused to EGFP (enhanced green fluorescent protein) suppressed LTD in a wild-type PN. These results suggest that 865ϳ871 aa of GluR␦2 play an essential role in LTD. We next identified protein interacting with C kinase 1 (PICK1) as a molecule interacting with the membrane-proximal C-terminal region of GluR␦2 by yeast two-hybrid screening. PICK1 plays an essential role in LTD. It colocalized with GluR␦2 at spines of PNs, and immunoprecipitation assays showed that GluR␦2 bound to PICK1 mainly through 865-871 aa. These results indicate that 865-871 aa of GluR␦2 are essential for both LTD and interaction with PICK1, and suggest that interaction between GluR␦2 and PICK1 might be critical for the induction of LTD.

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“…plays an important role in the formation and maintenance of the PF-PC synapse (Guastavino et al, 1990;Kashiwabuchi et al, 1995;Kurihara et al, 1997;Lalouette et al, 2001;Takeuchi et al, 2005) through its selective expression at this synapse (Araki et al, 1993;Lomeli et al, 1993;Takayama et al, 1995;Landsend et al, 1997) and specific interaction of its N-terminal domain with presynaptic molecule neurexin through Cbln1 released from granule cells (Kashiwabuchi et al, 1995;Kurihara et al, 1997;Lalouette et al, 2001;Yuzaki, 2009;Matsuda et al, 2010;Uemura et al, 2010). Primary defects in GluRδ2-KO mice occur in the connectivity of PF-PC synapses, as manifested by the emergence of free spines and mismatching of pre-and postsynaptic specialization (Guastavino et al, 1990;Kurihara et al, 1997;Lalouette et al, 2001).…”

Section: Application To Glurδ2-ko Micementioning

confidence: 99%

Development of an anatomical technique for visualizing the mode of climbing fiber innervation in Purkinje cells and its application to mutant mice lacking GluRδ2 and Cav2.1

Miyazaki

Watanabe

2010

Anat Sci Int

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In the adult cerebellum, a single climbing fiber (CF) innervates proximal dendrites of Purkinje cells (PCs). This mono-innervation is established by developmental elimination of surplus CFs through homosynaptic competition among multiply-innervating CFs and heterosynaptic competition between CFs and parallel fibers, i.e., granule cell axons innervating distal PC dendrites.Although developmental process of CF mono-innervation and its defects in mutant and experimental animal models have been extensively studied by electrophysiological techniques, relevant morphological information had been poorly understood, because of the lack of neuroanatomical methods to distinguish CFs of different neuronal origins. Soon after the identification of type 2 vesicular glutamate transporter (VGluT2) that selectively detects CF terminals in the molecular layer, we developed a novel method of combined anterograde tracer labeling and VGluT2 immunohistochemistry. This method enables us to identify the mode (mono-innervation vs. multiple innervation) of CF innervation and the site of multiple innervation. Since then, we have applied this method to various kinds of gene-manipulated mice manifesting ataxia and other cerebellar phenotypes. In this review, we summarize experimental procedures for the combined tracer/VGluT2 labeling method, and then introduce what we learned with this method when applied to studies on the role of GluRδ2 and Ca v 2.1 in CF mono-innervation. This method has provided informative anatomical correlates to electrophysiological data and vice versa, and will extend our knowledge on the molecular and cellular mechanisms for development, plasticity, degeneration, and repair of the CF-PC projection system.

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Control of Synaptic Connection by Glutamate Receptor δ2 in the Adult Cerebellum

Cited by 113 publications

References 54 publications

GluRδ2 Assembles Four Neurexins intoTrans-Synaptic Triad to Trigger Synapse Formation

GluRδ2 Assembles Four Neurexins intoTrans-Synaptic Triad to Trigger Synapse Formation

Membrane-Proximal Region of Glutamate Receptor δ2 Subunit Is Critical for Long-Term Depression and Interaction with Protein Interacting with C Kinase 1 in a Cerebellar Purkinje Neuron

Development of an anatomical technique for visualizing the mode of climbing fiber innervation in Purkinje cells and its application to mutant mice lacking GluRδ2 and Cav2.1

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