LTP requires a reserve pool of glutamate receptors independent of subunit type

Granger, Adam J.; Shi, Yun; Lü, Wei; Cerpas, Manuel; Nicoll, Roger A.

doi:10.1038/nature11775

Cited by 290 publications

(346 citation statements)

References 42 publications

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“…The concept that subunit composition is the defining factor in the AMPAR trafficking underlying plasticity has been called into question by acute AMPAR subunit knockdown and molecular replacement studies 18,19 . Contrary to expectation, using a strong LTP induction protocol it was reported that no specific AMPAR subunit is required for LTP.…”

Section: Subunit Independent Traffickingmentioning

confidence: 99%

“…However, as discussed below, this model has been challenged by several recent reports. These include reports interrogating the roles in activity-dependent trafficking and synaptic plasticity of specific AMPAR subunits 18,19 , their C-terminal tails and PDZ ligands 20,21 and changes to their phosphorylation status 22 . Taken together these findings have initiated a reappraisal of the core mechanisms underlying synaptic incorporation of AMPARs.…”

Section: Subunit-specific Traffickingmentioning

confidence: 99%

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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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Section: Subunit Independent Traffickingmentioning

confidence: 99%

Section: Subunit-specific Traffickingmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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“…, 2 0 0 7 ) . A l s o s e v e r a l m e c h a n i s m s t o counterbalance impaired Hebbian plasticity exist (Granger et al, 2013). From this perspective, it is not surprising that, in the absence of GluA4, no dramatic defects in overall circuit development were detected; no differences in either mEPSC frequency or amplitude were observed in CA1 pyramidal neurons between WT and GluA4-/-mice.…”

Section: Physiological Significance Of Glua4-dependent Plasticity In mentioning

confidence: 99%

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

et al. 2017

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Synaptic recruitment of AMPA receptors (AMPARs) represents a key postsynaptic mechanism driving functional development and maturation of glutamatergic synapses. At immature hippocampal synapses, PKA-driven synaptic insertion of GluA4 is the predominant mechanism for synaptic reinforcement. However, the physiological significance and molecular determinants of this developmentally restricted form of plasticity are not known. Here we show that PKA activation leads to insertion of GluA4 to synaptic sites with initially weak or silent AMPAR-mediated transmission. This effect depends on a novel mechanism involving the extreme C-terminal end of GluA4, which interacts with the membrane proximal region of the C-terminal domain to control GluA4 trafficking. In the absence of GluA4, strengthening of AMPAR-mediated transmission during postnatal development was significantly delayed. These data suggest that the GluA4-mediated activation of silent synapses is a critical mechanism facilitating the functional maturation of glutamatergic circuitry during the critical period of experience-dependent fine-tuning.

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“…GluA1 and GluA4 containing AMPAR trafficking is mediated by interaction of GluA1-MPR and GluA4-MPR with intracellular proteins, such as protein 4.1N and PKCγ (Shen et al, 2000;Coleman et al, 2003;Correia et al, 2003;Chen et al, 2005;Gomes et al, 2007;Lin et al, 2009). However, of note a recent study has shown that the MPR of GluA1 is not needed for protein trafficking or LTP in hippocampal CA1 (Granger et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The Membrane Proximal Region of AMPA Receptors in Lateral Amygdala is Essential for Fear Memory Formation

Ganea

Dines

Basu

et al. 2015

Neuropsychopharmacol

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The membrane proximal region (MPR) of AMPA receptor (AMPAR) is needed for receptor trafficking and synaptic plasticity. However, its roles in long-term memory formation are not known. To assess the possible roles of AMPAR-MPR in rat lateral amygdala (LA) in shortand long-term fear memory formation, we used glutamate receptors (GluAs)-MPR competitive peptides MPR(DD) and MPR(AA). The MPR(DD) peptide is derived from GluA1 MPR and was previously shown to impair synaptic plasticity and to inhibit GluA1 containing AMPAR insertion into the synapse in an activity-dependent manner. The MPR(AA) peptide is derived from GluA2/4 MPR, and this receptor fragment was shown to be essential for GluA4 protein interaction needed for its insertion into the neuronal membrane and synapse. The peptides were linked to a TAT peptide (TAT-MPR(DD) and TAT-MPR(AA)) to facilitate internalization into LA cells. Infusion of the TAT-MPR(DD) peptide into LA 30 min before fear conditioning led to a significant impairment of long-term fear memory formation. Injection of TAT-MPR(DD) peptide into LA 30 min before fear conditioning impaired short-term fear memory formation. The TAT-MPR(DD) peptide had no effect on memory retrieval when injected into LA 30 min before fear memory test. Infusion of the TAT-MPR(AA) peptide into LA 30 min before fear conditioning led to a significant impairment of long-term fear memory formation. In contrast, the TAT-MPR(AA) had no effect on short-term fear memory formation. A TAT-control peptide had no effect on short-or longterm fear memory. These results show that the AMPAR-MPR in LA is needed for fear memory formation and that the MPR region of GluA1 is essential for acquisition of memory, whereas the MPR region of GluA4 is essential for long-term fear memory consolidation.

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LTP requires a reserve pool of glutamate receptors independent of subunit type

Cited by 290 publications

References 42 publications

Synaptic AMPA receptor composition in development, plasticity and disease

Synaptic AMPA receptor composition in development, plasticity and disease

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

The Membrane Proximal Region of AMPA Receptors in Lateral Amygdala is Essential for Fear Memory Formation

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