Synaptic Scaling Requires the GluR2 Subunit of the AMPA Receptor

Gainey, Melanie; Hurvitz-Wolff, Jennifer R.; Lambo, Mary E.; Turrigiano, Gina G.

doi:10.1523/jneurosci.3753-08.2009

Cited by 214 publications

(258 citation statements)

References 51 publications

(97 reference statements)

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“…GRIP1 was necessary for synaptic scaling, because scaling up was prevented by shRNA-mediated knock down (KD) of endogenous GRIP1 and rescued by replacement with an RNAi-insensitive (RNAiI) GRIP1 but not a GRIP1 mutant that lacks the GluA2 interaction domain. We showed previously that GluA2 KD blocks synaptic scaling (12). Here, we show that synaptic scaling after GluA2 KD can be rescued by wild-type (RNAiI) GluA2 or point mutants that do not interfere with GRIP1 binding but not by GluA2 point mutants (Y876E and S880E) that reduce GluA2-GRIP1 binding, strongly suggesting that GRIP1 mediates synaptic scaling through interactions with GluA2.…”

supporting

confidence: 51%

“…We showed previously that the GluA2 C-tail is required for TTX-induced synaptic scaling up (12). Here, we wished to determine the role of the GluA2 C-tail binding protein, GRIP1, in synaptic scaling.…”

Section: Resultsmentioning

confidence: 99%

“…During synaptic scaling up in response to action potential blockade, synaptic strength is increased through enhanced synaptic accumulation of GluA1 and GluA2-containing AMPAR (5,(10)(11)(12)(13) and requires the C-terminal domain of the GluA2 subunit (12), but which subunit-specific interactions underlie synaptic scaling remain controversial (12,14). Several trafficking proteins are known to interact with the GluA2, but not the GluA1, C-tail, including glutamate receptor interacting protein-1 (GRIP1) (15) and protein interacting with C-kinase-1 (PICK1) (16).…”

mentioning

confidence: 99%

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Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

Gainey

Tatavarty

Nahmani

et al. 2015

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

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Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up.P roper development of neuronal circuits, as well as efficient information storage during learning and memory, are thought to depend upon the presence of homeostatic mechanisms that stabilize neuronal excitability (1-3). One such mechanism is synaptic scaling, which compensates for perturbations in average firing by scaling up or down the postsynaptic strength of all of a neuron's excitatory synapses (4). Synaptic scaling is a cell-autonomous process in which neurons detect changes in their own firing through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of AMPA receptors (AMPAR) at synaptic sites and thus increase or decrease synaptic strength (4-6). Despite great recent interest, the AMPA receptor-trafficking events that underlie synaptic scaling remain largely obscure. Defects in synaptic scaling have been postulated to contribute to disorders as diverse as Alzheimer's disease (7) and epilepsy (8), so illuminating the underlying AMPAR trafficking steps could shed light into the genesis of a wide range of neurological disorders.Most neocortical AMPAR are heteromeric receptors composed of both GluA1 and GluA2 subunits, which have unique phosphorylation sites and interact with distinct trafficking proteins (9). During synaptic scaling up in response to action potential blockade, synaptic strength is increased through enhanced synaptic accumulation of GluA1 and GluA2-containing AMPAR (5, 10-13) and requires the C-terminal domain of the GluA2 subunit (12), but which subunit-specific interactions underlie synaptic scaling remain controversial (12,14). Several trafficking proteins are known to interact with the GluA2, but not the GluA1, C-tail, including glutamate recepto...

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supporting

confidence: 51%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

Gainey

Tatavarty

Nahmani

et al. 2015

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

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“…It should be noted, however, that despite these reports, several studies have failed to detect the specific incorporation of CP-AMPARs during homeostatic scaling, e.g. 65 , suggesting this specific incorporation of CP-AMPARs may be dependent on the synapse, developmental stage and mode of induction. Thus, as for the proposed involvement of CP-AMPARs in LTP, the differential recruitment of CP-AMPAR during homeostatic scaling remains controversial.…”

Section: Cp-ampars In Synaptic Plasticitymentioning

confidence: 98%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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“…AMPAR trafficking, binding, and modification are highly subunit-specific. It has been shown that the GluA2 subunit, but not GluA1, is required for inactivity-induced scaling, and the C-terminal domain is crucial (10). Many molecules known to regulate AMPAR trafficking, including AKAP5, Arc, TNFα, β3 integrins, PSD-95, and PICK1, are all involved in or required for synaptic scaling in neuronal cultures (11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

GRIP1 is required for homeostatic regulation of AMPAR trafficking

Tan

Queenan

Huganir

2015

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

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Homeostatic plasticity is a negative feedback mechanism that stabilizes neurons during periods of perturbed activity. The best-studied form of homeostatic plasticity in the central nervous system is the scaling of excitatory synapses. Postsynaptic AMPA-type glutamate receptors (AMPARs) can be inserted into synapses to compensate for neuronal inactivity or removed to compensate for hyperactivity. However, the molecular mechanisms underlying the homeostatic regulation of AMPARs remain elusive. Here, we show that the expression of GRIP1, a multi-PDZ (postsynaptic density 95/discs large/zona occludens) domain AMPAR-binding protein, is bidirectionally altered by neuronal activity. Furthermore, we observe a subcellular redistribution of GRIP1 and a change in the binding of GRIP1 to GluA2 during synaptic scaling. Using a combination of biochemical, genetic, and electrophysiological methods, we find that loss of GRIP1 blocks the accumulation of surface AMPARs and the scaling up of synaptic strength that occur in response to chronic activity blockade. Collectively, our data point to an essential role of GRIP1-mediated AMPAR trafficking during inactivity-induced synaptic scaling.synaptic scaling | postsynaptic density | glutamate receptor | PDZ domain

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Synaptic Scaling Requires the GluR2 Subunit of the AMPA Receptor

Cited by 214 publications

References 51 publications

Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

Synaptic AMPA receptor composition in development, plasticity and disease

GRIP1 is required for homeostatic regulation of AMPAR trafficking

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