TARPs γ‐2 and γ‐7 are essential for AMPA receptor expression in the cerebellum

Yamazaki, Maya; Fukaya, Masahiro; Hashimoto, Kouichi; Yamasaki, Miwako; Teräs, Mika; Itakura, Makoto; Abe, Manabu; Natsume, Rie; Takahashi, Masami; Kano, Masanobu; Sakimura, Kenji; Watanabe, Masahiko

doi:10.1111/j.1460-9568.2010.07254.x

Cited by 81 publications

(98 citation statements)

References 70 publications

(180 reference statements)

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“…We used the following primary antibodies: mouse monoclonal anti-Cre recombinase (Millipore Bioscience Research Reagents, MAB3120), goat anti-calbindin (Miura et al, 2006), rabbit anti-GluA1, GluA2, and GluA3 (Yamazaki et al, 2010), guinea-pig anti-GluA4 (Nagy et al, 2004), rabbit anti-GluR␦2 (Takeuchi et al, 2005), anti-metabotropic glutamate receptor 1 (mGluR1) (Tanaka et al, 2000), rabbit anti-parvalbumin (Miura et al, 2006), rabbit anti-neurogranin (Miyazaki et al, 2011), rabbit anti-PSD-93 and PSD-95 , rabbit anti-stargazin (TARP␥2) (Yamazaki et al, 2010), rabbit anti-type 1 vesicular glutamate transporter (VGluT1) (Miyazaki et al, 2003), and guinea pig anti-VGluT2 (Miyazaki et al, 2003).…”

Section: Methodsmentioning

confidence: 99%

“…First, we tested the specificity of immunogold labeling for GluA subunits, because GluA1-3 antibodies, which have been produced recently (Yamazaki et al, 2010) and used in the present study, gave much higher immunogold labeling than those produced previously (Takeuchi et al, 2005). No significant labeling was seen for any GluA subunits in the corresponding GluA-KO mice (Fig.…”

Section: Target-and Input-dependent Regulations Of Synaptic Glua Subumentioning

confidence: 99%

“…In the cerebellum, PSD-95 and stargazin are expressed in both PCs and basket/stellate cells Yamazaki et al, 2010), and PSD-93 is predominantly expressed in PCs (Fukaya et al, 1999;Roche et al, 1999;McGee et al, 2001). We examined whether the increase of synaptic GluA expression accompanied that of such interacting proteins in GluR␦2-KO mice.…”

Section: Psd-93 Psd-95 and Stargazin Also Increase At Glur␦2-ko Pf mentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Target-and Input-dependent Regulations Of Synaptic Glua Subumentioning

confidence: 99%

Section: Psd-93 Psd-95 and Stargazin Also Increase At Glur␦2-ko Pf mentioning

confidence: 99%

See 1 more Smart Citation

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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“…Transmembrane AMPAR regulatory proteins (TARPs) are candidate molecules that deserve attention (29). TARP γ-2, which is highly phosphorylated in its basal state, was dephosphorylated during chemically induced LTD in cerebellar slices (30).…”

Section: Discussionmentioning

confidence: 99%

Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus

Yamaguchi

Itohara

Ito

2016

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

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Long-term depression (LTD) of synaptic transmission from parallel fibers (PFs) to a Purkinje cell (PC) in the cerebellum has been considered to be a core mechanism of motor learning. Recently, however, discrepancies between LTD and motor learning have been reported in mice with a mutation that targeted the expression of PF-PC LTD by blocking AMPA-subtype glutamate receptor internalization regulated via the phosphorylation of AMPA receptors. In these mice, motor learning behavior was normal, but no PF-PC LTD was observed. We reexamined slices obtained from these GluA2 K882A and GluA2 Δ7 knockin mutants at 3-6 mo of age. The conventional protocols of stimulation did not induce LTD in these mutant mice, as previously reported, but surprisingly, LTD was induced using certain modified protocols. Such modifications involved increases in the number of PF stimulation (from one to two or five), replacement of climbing fiber stimulation with somatic depolarization (50 ms), filling a patch pipette with a Cs + -based solution, or extension of the duration of conjunction. We also found that intracellular infusion of a selective PKCα inhibitor (Gö6976) blocked LTD induction in the mutants, as in WT, suggesting that functional compensation occurred downstream of PKCα. The possibility that LTD in the mutants was caused by changes in membrane resistance, access resistance, or presynaptic property was excluded. The present results demonstrate that LTD is inducible by intensified conjunctive stimulations even in K882A and Δ7 mutants, indicating no contradiction against the LTD hypothesis of motor learning.cerebellum | LTD | Marr-Albus-Ito hypothesis | motor-learning | slice

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“…These proteins play an essential role in tethering AMPA-type glutamate receptors at the synapse, and also exert complex control over surface expression of functional receptors (Dakoji et al, 2003;Yamazaki et al, 2010). Auxiliary proteins regulate the function of AMPA receptors, with both positive and negative modulation of gating (von Engelhardt et al, 2010;Priel et al, 2005;McGee et al, 2015;Rouach et al, 2005), as well as control over permeation and block (Soto et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Control of AMPA Receptor Activity by the Extracellular Loops of Auxiliary Proteins

Eibl

Riva

Volkmer

et al. 2018

Biophysical Journal

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At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs g2 and g8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of g2 and g8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of g2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

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TARPs γ‐2 and γ‐7 are essential for AMPA receptor expression in the cerebellum

Cited by 81 publications

References 70 publications

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

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

Reassessment of long-term depression in cerebellar Purkinje cells in mice carrying mutated GluA2 C terminus

Control of AMPA Receptor Activity by the Extracellular Loops of Auxiliary Proteins

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