A Developmental Switch of AMPA Receptor Subunits in Neocortical Pyramidal Neurons

Kumar, Sanjay S.; Bacci, A.; Kharazia, Viktor; Huguenard, John R.

doi:10.1523/jneurosci.22-08-03005.2002

Cited by 319 publications

(325 citation statements)

References 62 publications

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“…This result is consistent with predominant expression of GluA4 'flip' during early development (Monyer et al, 1991). Additionally, the data suggest that the observed developmental increase in the decay time of AMPA EPSCs depends on mechanisms that operate in the absence of GluA4, such as alternative splicing (Monyer et al, 1991), heteromerization with GluA2 (Kumar et al 2002, Ho et al 2007 or increased dendritic filtering (Hausser and Roth, 1997).…”

Section: Maturation Of Ampar-mediated Transmission Is Perturbed In Thsupporting

confidence: 67%

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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Section: Maturation Of Ampar-mediated Transmission Is Perturbed In Thsupporting

confidence: 67%

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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“…Together, our results argue against NMDArs being the principal source of increases in intracellular Ca 2ϩ needed for calpain activation with the manipulations described here. However, AMPArs are Na ϩ channels and are, by and large, impermeable to Ca 2ϩ ions (Lomeli et al, 1994;Jensen et al, 1998;Carlson et al, 2000;Iizuka et al, 2000;Krampfl et al, 2002;Kumar et al, 2002). Interestingly, elevated intracellular Na ϩ levels can increase Ca 2ϩ release from intracellular stores (Hoyt et al, 1998;Zhang and Lipton 1999), thus CX614-induced increases in AMPAr function and the resulting depolarization may contribute to increased intracellular levels of Ca 2ϩ .…”

Section: Discussionmentioning

confidence: 99%

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Jourdi

Lü²,

Yanagihara³

et al. 2005

J Pharmacol Exp Ther

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Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2Љ,1Љ-3Ј,2Ј]1,3-oxazino[6Ј,5Ј-5,4]-benzo[e]1,4-dioxan 10-one], a positive ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.AMPA-type glutamate receptors (AMPAr) mediate most of the fast excitatory neurotransmission in the mammalian central nervous system. Several recent studies have implicated the cycling of these receptors into and out of the synaptic compartment in important neurophysiological phenomena such as long-term potentiation (LTP) and long-term depression (LTD) in support of our initial hypothesis (Baudry and

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“…This regulated ER exit limits the types and numbers of AMPARs available for synapses and, by disfavouring GluA2 homotetramer formation, maintains a stable ER pool of edited GluA2, which is required for the formation of GluA2-containing heteromeric AMPARs later in development 80,81 . Importantly, because it takes longer for edited GluA2 to incorporate into assembling AMPARs, the reduced ER dwell time of unedited GluA2 facilitates the rapid forward traffic and surface expression of CP-AMPARs during synapse formation and stablisation early in development 82 . As the CNS matures, developmentally controlled RNA editing of GluA2 progressively hinders its homodimerisation and retards ER exit, which then increases the incorporation of GluA2 into AMPAR heteromers, consistent with the switch from CP-AMPARs to CI-AMPARs during brain development.…”

Section: Rna Editing Ampar Assembly and Er Exitmentioning

confidence: 99%

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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A Developmental Switch of AMPA Receptor Subunits in Neocortical Pyramidal Neurons

Cited by 319 publications

References 62 publications

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

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

Prolonged Positive Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Induces Calpain-Mediated PSD-95/Dlg/ZO-1 Protein Degradation and AMPA Receptor Down-Regulation in Cultured Hippocampal Slices

Synaptic AMPA receptor composition in development, plasticity and disease

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