Cerebellar Long-Term Depression Requires PKC-Regulated Interactions between GluR2/3 and PDZ Domain–Containing Proteins

Xia, Jun; Chung, Hee Jung; Wihler, Cornelia; Huganir, Richard L.; Linden, David J.

doi:10.1016/s0896-6273(00)00128-8

Cited by 362 publications

(337 citation statements)

References 61 publications

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“…Likewise Brebner et al (2005) demonstrate that Tat-GluR2 3Y blocks the induction of LTD in nucleus accumbens neurons in an in vitro slice preparation. This is consistent with other studies that have implied a role for AMPA receptor endocytosis in mediating LTD (Wang and Linden, 2000;Xia et al, 2000). Of particular relevance to the present study is the recent report that i.v.…”

Section: Blockade Of Ampa Receptor Endocytosis Does Not Effect the Acsupporting

confidence: 94%

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

Dalton

Wang

Floresco

et al. 2007

Neuropsychopharmacol

145

135

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Synaptic plasticity in the form of long-term potentiation (LTP) plays a critical role in the formation of a Pavlovian fear association. However, the role that synaptic plasticity plays in the suppression of a learned fear response remains to be clarified. Here, we assessed the role that long-term depression (LTD) plays in the acquisition, expression, and extinction of a conditioned fear response. We report that blockade of LTD with a GluR2-derived peptide (Tat-GluR2 3Y ; 1.5 mmol/kg, i.v.) that blocks regulated a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptor endocytosis during an initial extinction training session disrupted both the expression and recall of extinction learning. A similar impairment of extinction during training, but not recall, was observed when NMDA receptor-dependent LTD was inhibited through the selective blockade of NMDA NR2B receptors with Ro 25-6981. In contrast, blockade of LTD with Tat-GluR2 3Y during fear conditioning or during a fear recall test did not effect the expression or recall of either contextual or cue-induced conditioned fear. Similarly, administration of Tat-GluR2 3Y prior to an extinction recall test did not affect spontaneous recovery or rate of re-extinction in previously extinguished rats. These data demonstrate that AMPA receptor endocytosis does not mediate acquisition or expression of conditioned fear, but may play a role in the extinction of fear memories. Furthermore, these findings suggest that LTD may be a molecular mechanism that facilitates the selective modification of a learned association while leaving intact the ability to form a new memory.

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Section: Blockade Of Ampa Receptor Endocytosis Does Not Effect the Acsupporting

confidence: 94%

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

Dalton

Wang

Floresco

et al. 2007

Neuropsychopharmacol

145

135

View full text Add to dashboard Cite

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“…Removal of the PDZ binding site from GluR2 reduces the accumulation of AMPAR levels at the synapse 42 . Moreover, disruption of the interaction between GluR2 and GluR3 and PDZ domains has been reported to block LTD in the hippocampus 43 and cerebellum 44 . These effects appear to be regulated by protein kinase C (PKC), which reduces binding of GluR2 to GRIP and ABP, but not PICK1, by phosphorylating AMPARs at a serine residue (Ser-880) near the C-terminal 45 .…”

Section: When Do Ampars Take a Break?mentioning

confidence: 99%

“…Moreover, the GluR2-PICK1 interaction appears to be required for cerebellar LTD (Ref. 44 ), but hippocampal LTD requires the GluR2-GRIP/ABP interaction 43 . Given these complexities, a comprehensive model seems far off; nevertheless, the evidence is strong for regulation of AMPAR localization by specific protein-protein interactions at the PDZ binding site.…”

Section: When Do Ampars Take a Break?mentioning

confidence: 99%

“…This result could indicate that some of the receptors internalized by LTD come from a stabilized pool, or alternatively that AMPAR-PDZ interactions do not exclude AMPARs from the recycling pool. It is interesting to note that in cerebellar LTD (an NMDARindependent process), interference with the clathrin endocytotic complex or PDZ-domain interactions also block changes in synaptic efficacy 44,51 . This suggests that the dynamic modulation of the number of postsynaptic receptors is a mechanism to regulate synaptic strength shared by several forms of long-term synaptic plasticity.…”

Section: Ltdmentioning

confidence: 99%

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Restless AMPA receptors: implications for synaptic transmission and plasticity

Lüscher

Frerking

2001

Trends in Neurosciences

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A central assumption in neurobiology holds that changes in the strength of individual synapses underlie changes in behavior. This concept is widely accepted in the case of learning and memory where LTP and LTD are the most compelling cellular models. It is therefore of great interest to understand, on a molecular level, how the brain regulates the strength of neuronal connections. We review a large body of evidence in support of the very straightforward regulation of synaptic strength by changing the number of postsynaptic receptors, and discuss the molecular machinery required for insertion and removal of AMPA receptors.The hypothesis that insertion of AMPA receptors (AMPARs) underlies the increase of synaptic strength associated with LTP was put forward almost 20 years ago 1 , but was largely ignored until the mid-1990s, resurfacing with quantal analysis of LTP (Ref. 2 ). However, only recently has it become the subject of direct experimental scrutiny.The spark for the myriad of research published in the past few years in the field was experiments conducted independently by two groups 3,4 , in which single connections between CA3 axons and CA1 pyramidal cells in acute hippocampal slices were functionally isolated and in some cases yielded only responses from NMDA receptors (NMDARs) and not AMPARs. Inducing LTP, however, caused the appearance of AMPAR mediated excitatory postsynaptic currents (EPSCs). This led to the proposal that a fraction of 'silent' synapses contain only NMDARs, and thus are functionally inactive at normal resting potential, but maintain the capability to undergo LTP, which would be expressed by AMPAR insertion. Although alternative explanations for these results have been proposed 5,6 , synapses with NMDARs but not AMPARs have now been directly identified anatomically in cultured hippocampal neurons using immunofluorescence 7,8 and with immuno-gold preparations visualized by electron microscopy in hippocampal slices 9-11 .AMPARs move from the cytoplasm to the surface and back again Constitutive recyclingIf LTP expression is caused by postsynaptic AMPAR insertion, it must be the case that AMPARs can be inserted into and removed from the postsynaptic membrane on a relatively rapid time scale. To test this experimentally, CA1 pyramidal cells in acute hippocampal slices * Christian.Luscher@medecine.unige.ch.

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“…Normally, PKCα phosphorylates Ser880 and thereby detaches the AMPA-subtype glutamate receptors (AMPARs) from a synaptic scaffold protein, GRIP1/2; consequently, AMPARs are internalized. On the other hand, PDZ ligands and phosphorylation by other kinases remain functionally intact (13)(14)(15)(16)(17). The other is the GluA2 Δ7 KI (hereafter, Δ7) genotype, which lacks the last 7 amino acids of the C-terminal tail of GluA2.…”

mentioning

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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Cerebellar Long-Term Depression Requires PKC-Regulated Interactions between GluR2/3 and PDZ Domain–Containing Proteins

Cited by 362 publications

References 61 publications

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

Restless AMPA receptors: implications for synaptic transmission and plasticity

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

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