Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD

Beattie, Eric C.; Carroll, Reed C.; Yu, Xiang; Morishita, Wade; Yasuda, Hiroki; Zastrow, Mark von; Malenka, Robert C.

doi:10.1038/81823

Cited by 667 publications

(697 citation statements)

References 51 publications

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“…In agreement with the electrophysiology data, our results show that NMDAR‐dependent internalisation of GluA2‐containing AMPARs, which is thought to be the major mechanism for LTD (Beattie et al , 2000; Anggono & Huganir, 2012), is unaffected by Ago2 S387 mutations, emphasising that distinct pathways control structural and functional plasticity.…”

Section: Discussionsupporting

confidence: 90%

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

et al. 2018

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MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA‐induced silencing complex (RISC), underpinning a powerful mechanism for fine‐tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)‐dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt‐dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR‐134. Furthermore, NMDAR‐dependent down‐regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho‐regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA‐mediated translational repression to control dendritic spine morphology.

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Section: Discussionsupporting

confidence: 90%

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

et al. 2018

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“…NMDAR activation induces AMPAR internalization and recycling. This internalization requires the activation of protein phosphatases 13 , one of which is the Ca 2+ -dependent protein phosphatase calcineurin 23 . The crucial dephosphorylated target is still unknown.…”

Section: Activity Drives Removal Of Amparsmentioning

confidence: 99%

“…Some evidence suggests that ligand binding by itself is a trigger for endocytosis 13,14 , but it has also been reported that AMPAR-dependent internalization is caused by an AMPAR-dependent depolarization, which then induces Ca 2+ influx through activation of voltage-gated Ca 2+ channels 14,23,27 , and would presumably act through the same mechanisms as NMDA-induced internalization. The ligand-dependent AMPAR internalization is not dependent on intracellular Ca 2+ and is not accompanied by dephosphorylation of GluR1; notably, AMPARs internalized by this ligand-dependent mechanism are targeted to lysosomes rather than recycled 14 .…”

Section: Activity Drives Removal Of Amparsmentioning

confidence: 99%

“…The mechanisms underlying this internalization remain largely unknown. Calcineurin could possibly be involved 14 , but this has been contested 23 . Curiously, AMPARs internalized by insulin are initially targeted to early endosomes, but are then sorted into a separate, non-lysosomal internal compartment 14 .…”

Section: Activity Drives Removal Of Amparsmentioning

confidence: 99%

“…Depolymerization of actin leads to a loss of AMPARs from the surface 27,40 and a decrease in synaptic efficacy 41 . Conversely, stabilization of actin has been reported to prevent glutamate-induced AMPAR internalization 27 ; however, this result is controversial 23 , and interpretation is further complicated by the observation that actin stabilization also interferes to some degree with the endocytotic process 27 .…”

Section: When Do Ampars Take a Break?mentioning

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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Glutamatergic Synapses: Molecular Organisation

Siddoway

Hou

Xia

2011

Encyclopedia of Life Sciences

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One of the best understood and highly organised synapses is excitatory glutamatergic synapses. These synapses consist of post‐synaptic ionotropic glutamate receptors and pre‐synaptic glutamate localised inside pre‐synaptic vesicles. Glutamate binds to α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid subtype glutamate receptors, giving rise to synaptic transmission. However, N ‐methyl‐ d ‐aspartate subtype glutamate receptors function to induce the change in synaptic transmission, also known as the synaptic plasticity that underlies learning and memory. The subtypes and subunits of glutamate receptors exhibit distinct biophysical properties and play distinct physiological roles critical for synaptic function. The molecular organisation of the synapse includes intracellular scaffolding proteins, intercellular cell adhesion molecules to anchor synaptic architecture and a variety of signalling proteins (kinases, phosphatases, etc.). They function to support and/or mediate the cellular processes critical for synaptic transmission and plasticity, whereas their malfunction leads to diseases where synaptic plasticity is lost, such as Alzheimer disease and mental retardation. Key Concepts: Glutamatergic synapses are critical for our brain function. Synaptic plasticity is critical for proper neuronal circuit formation. Synaptic plasticity is the cellular model for learning, memory and other experience‐dependent brain functions. History of neuronal activity plays a significant role in synaptic protein composition, which in turn governs synapse‐to‐nucleus signalling. Scaffolding proteins, in addition to signalling proteins and receptors, are critical for synaptic plasticity. Extrasynaptic NMDA receptor signalling plays distinct roles from synaptic NMDA receptor signalling.

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Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD

Cited by 667 publications

References 51 publications

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

Restless AMPA receptors: implications for synaptic transmission and plasticity

Glutamatergic Synapses: Molecular Organisation

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