New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function

Hirai, Hirokazu; Lavstsen, Thomas; Mikawa, Sumiko; Torashima, Takashi; Yanagihara, Dai; Kasaura, Tsuyoshi; Miyamoto, Akihiro; Yuzaki, Michisuke

doi:10.1038/nn1086

Cited by 122 publications

(112 citation statements)

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“…This absence of depression after CS does not result from PC dialysis nor from the prior reduction of eEPSC amplitude because comparable partial reduction of eEPSC amplitude by a noncompetitive AMPAR antagonist (GYKI-53655) perfused for 20 min did not prevent CS-induced LTD (Fig. 2 A Inset), as recently shown (37). Note that we selected cell pairs for which the eEPSC amplitude was still at least 35 pA after the depression induced by fostriecin͞GYKI, to allow better detection of any further depression.…”

Section: Resultssupporting

confidence: 77%

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Lavstsen

Endo

Sakai

et al. 2003

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

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Section: Resultssupporting

confidence: 77%

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Lavstsen

Endo

Sakai

et al. 2003

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

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“…At PF-PC synapses, GluR␦2 plays a key role in the formation and maintenance of PF-PC synapses (Kashiwabuchi et al, 1995;Kurihara et al, 1997;Lalouette et al, 2001;Takeuchi et al, 2005;Matsuda et al, 2010;Uemura et al, 2010). Furthermore, GluR␦2 regulates endocytosis of AMPARs (Hirai et al, 2003) and mediates long-term depression (LTD) at PF-PC synapses (Kashiwabuchi et al, 1995). These characteristics led us to hypothesize that GluR␦2 could also be involved in the input pathway-dependent biased distribution of AMPARs at PC synapses.…”

Section: Introductionmentioning

confidence: 99%

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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“…Thus, palmitoylated and non-palmitoylated isoforms of ABP/GRIP2 could be involved in the trafficking of AMPA receptors during synaptic plasticity. Unlike AMPA receptors, GluR␦2 is mainly localized at plasma membranes (17); however, it is rapidly endocytosed when intracellular Ca 2ϩ levels are elevated by synaptic activities (26), and the presence of GluR␦2 at postsynaptic membranes is thought to play an essential role in controlling AMPA receptor endocytosis and LTD induction in Purkinje cells (7). Therefore, although the distribution and functions of endogenous Sand L-delphilin isoforms need to be further clarified in vivo, these isoforms may be involved in certain aspects of synaptic plasticity by providing two separate GluR␦2 anchorages (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence indicate that LTD is caused by an activity-dependent decrease in the number of postsynaptic AMPA receptors (5,6). Interestingly, the application of an antibody specific for the extracellular region of GluR␦2 to cultured Purkinje cells induced the endocytosis of AMPA receptors in Purkinje cells and abrogated subsequent LTD (7). These results indicate that GluR␦2 plays another unique role at PF-Purkinje cell synapses, the regulation of postsynaptic AMPA receptor endocytosis.…”

mentioning

confidence: 89%

Characterization of the δ2 Glutamate Receptor-binding Protein Delphilin

Matsuda

Gladding

et al. 2006

Journal of Biological Chemistry

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The glutamate receptor ␦2 (GluR␦2) is predominantly expressed at parallel fiber-Purkinje cell postsynapses and plays crucial roles in synaptogenesis and synaptic plasticity. Although the mechanism by which GluR␦2 functions remains unclear, its lack of channel activity and its role in controlling the endocytosis of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors have suggested that GluR␦2 may convey signals by interacting with intracellular signaling molecules. Among several proteins that interact with GluR␦2, delphilin is unique in that it is selectively expressed at parallel fiberPurkinje cell synapses and that, in addition to a single PDZ domain, it contains a formin homology domain that is thought to regulate actin dynamics. Here, we report a new isoform of delphilin, designated as L-delphilin, that has alternatively spliced N-terminal exons encoding an additional PDZ domain. Although original delphilin, designated S-delphilin, was palmitoylated at the N terminus, this region was spliced out in Ldelphilin. As a result, S-delphilin was associated with plasma membranes in COS cells and dendritic spines in hippocampal neurons, whereas L-delphilin formed clusters in soma and dendritic shafts. In addition, S-delphilin, but not L-delphilin, facilitated the expression of GluR␦2 on the cell surface. These results indicate that, like PSD-95 and GRIP/ABP, delphilin isoforms with differential palmitoylation and clustering capabilities may provide two separate intracellular and surface GluR␦2 pools and may control GluR␦2 signaling in Purkinje cells.Numerous spontaneous ataxic mutant mice occur as a result of null mutations in the gene encoding glutamate receptor ␦2 (GluR␦2), 2 a member of the ionotropic glutamate receptor family that is predominantly expressed at parallel fiber (PF)-Purkinje cell synapses in the cerebellum (1). Detailed morphological and electrophysiological analyses on GluR␦2-null mice suggest that GluR␦2 plays a crucial role in aligning and maintaining the postsynaptic density (PSD) with the presynaptic element at PF-Purkinje cell synapses (for reviews, see Ref.2). In addition, long-term depression (LTD) of PF-Purkinje cell transmission, which is thought to underlie a form of information storage in the cerebellum (3), is completely blunted in GluR␦2-null Purkinje cells (4). Several lines of evidence indicate that LTD is caused by an activity-dependent decrease in the number of postsynaptic AMPA receptors (5, 6). Interestingly, the application of an antibody specific for the extracellular region of GluR␦2 to cultured Purkinje cells induced the endocytosis of AMPA receptors in Purkinje cells and abrogated subsequent LTD (7). These results indicate that GluR␦2 plays another unique role at PF-Purkinje cell synapses, the regulation of postsynaptic AMPA receptor endocytosis. However, the mechanisms by which GluR␦2 plays these roles remain unclear; GluR␦2 does not contribute to normal excitatory postsynaptic currents (8).Excitatory synapses, in particular their PSDs, contain many PDZ domain-...

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New role of δ2-glutamate receptors in AMPA receptor trafficking and cerebellar function

Cited by 122 publications

References 38 publications

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

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

Characterization of the δ2 Glutamate Receptor-binding Protein Delphilin

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