Removal of AMPA Receptors (AMPARs) from Synapses Is Preceded by Transient Endocytosis of Extrasynaptic AMPARs

Ashby, Michael C.; Rue, Sarah A. De La; Ralph, G; Uney, James B.; Collingridge, Graham L.; Henley, Jeremy M.

doi:10.1523/jneurosci.1042-04.2004

Cited by 225 publications

(223 citation statements)

References 22 publications

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“…This movement of AMPA receptors following LTP induction is referred to as the regulated receptor pool (Contractor and Heinemann, 2002) (Figure 4). Following insertion at the synapse, AMPA receptors may cycle between the synapse and an intracellular domain, generating a pool of constitutive receptor complexes available for rapid reinsertion to the plasma membrane (Ashby et al, 2004) (Figure 4).…”

Section: Ampa Subtype Of Glutamate Receptor Traffickingmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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Section: Ampa Subtype Of Glutamate Receptor Traffickingmentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

106

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“…This conclusion is supported by the finding that the slowing effect of CTZ on the EPSC decay decreased with development, whereas that on the AMPA patch currents remained constant throughout development. This assumes that subsynaptic and extrasynaptic AMPARs are identical, which is supported by the functionally identical dendritic and somatic GluR channels in Purkinje cells (Häusser and Roth, 1997) and also by the recent reports that subsynaptic AMPA receptors are inserted and removed by lateral diffusion via extrasynaptic receptors (Borgdorff and Choquet, 2002;Ashby et al, 2004).…”

Section: Discussionmentioning

confidence: 91%

Mechanisms Underlying Developmental Speeding in AMPA-EPSC Decay Time at the Calyx of Held

Koike-Tani

Saitoh²,

Takahashi³

2005

J. Neurosci.

116

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The time course of synaptic conductance is important in temporal precision of information processing in the neuronal network. The AMPA receptor (AMPAR)-mediated EPSCs at the calyx of Held become faster in decay time as animals mature. To clarify how desensitization and deactivation of AMPARs contribute to developmental speeding of EPSCs, we compared the decay time of quantal EPSCs (qEPSCs) with the deactivation and desensitization times of AMPAR currents induced in excised patches by fast glutamate application (AMPA patch currents). Both the deactivation and desensitization times of AMPA patch currents became markedly faster from postnatal day 7 (P7) to P14 and changed little thereafter. In individual neurons, throughout development (P7-P21), the time constants of deactivation and fast desensitization in AMPA patch currents were similar to each other and close to the qEPSC decay time constant. Cyclothiazide (CTZ) abolished the fast desensitization, prolonged deactivation of AMPA patch currents, and slowed the decay time of EPSCs. The effects of CTZ on AMPA patch currents were unchanged throughout development, whereas its effect on EPSCs became weaker as animals matured. In single-cell reverse transcription-PCR analysis, glutamate receptor subunit 4 (GluR4) flop increased from P7 to P14 and changed little thereafter. At P7, the GluR4 flop abundance had an inverse correlation with the qEPSC decay time. These results together suggest that both desensitization and deactivation of AMPARs are involved in the EPSC decay time, but the contribution of desensitization decreases during postnatal development at the calyx of Held.

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“…Endocytosed AMPA-Rs are also localized at acidic compartments with a pH of ∼5.5 for endosomes (33). Green fluorescence thus reflects the surface pH-GluA2 and can be tracked to analyze the dynamics of its trafficking (34,35). pH-GluA2 cDNA was transfected into WT, GRIP2 KO, and GRIP1 and 2 DKO hippocampal neurons and visualized using live imaging techniques (35).…”

Section: Resultsmentioning

confidence: 99%

GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions

Mao

Takamiya

Thomas

et al. 2010

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

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PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein-protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 and GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the Ctermini of AMPA-R GluA2 and GluA3 subunits. Previous attempts to determine the cellular roles of GRIP1 and GRIP2 in neurons have been complicated by nonspecific reagents, and by the embryonic lethality of conventional GRIP1 KO mice. To circumvent these issues we developed a conditional targeted deletion strategy to knock out GRIP1 in postnatal neurons derived from GRIP2 KO mice. Loss of GRIP1 and 2 did not affect normal AMPA-R steadystate trafficking and endocytosis, but strikingly impaired activitydependent AMPA-R recycling. This previously uncharacterized role for GRIP1 appears to be mediated by novel interactions with the cellular trafficking machinery via the exocyst protein complex. Indeed, disruption of GRIP1-exocyst binding caused a strikingly similar deficit in AMPA-R recycling. Together these findings reveal a previously unidentified role for AMPA-R-GRIP1-exocyst protein complexes in activity-dependent AMPA-R trafficking.A MPA receptors conduct the majority of fast excitatory synaptic transmission in the mammalian central nervous system. Dynamic regulation of AMPA-R trafficking in and out of synapses modulates the efficacy of synaptic transmission and is crucial for synaptic plasticity (1-3). One major molecular mechanism that governs AMPA-R trafficking is the regulated interaction of intracellular C-termini of AMPA-R subunits with PSD-95/SAP90, DLG/ ZO-1 (PDZ) domain-containing proteins (4-7). The type II PDZ motifs of GluA2 and GluA3 C-termini interact with several PDZ domain-containing proteins, including PICK1 (6, 7) and the homologous GRIP1 and GRIP2 proteins (GRIP2 is also called ABP for AMPA-R binding protein) (4,5,8,9). GRIP proteins and PICK1 interact with GluA2 at the same site, but are differentially regulated by PKC-dependent phosphorylation of GluA2 Ser880 (10-12). In addition to GluA2/3, GRIP1 and 2 binds various signaling and cytoskeletal proteins, including EphB receptor tyrosine kinase, ephrinB ligands, α-liprin scaffolding protein, proteoglycan NG2, Fras1 and 2, GRIP1-associated protein 1 (GRASP-1), kinesin-1/KIF5 microtubule motor protein and matrix metalloproteinase 5 (13-19). Thus, GRIP proteins may serve to organize macromolecular complexes, linking AMPA-Rs and other membrane proteins to the cytoskeleton and membrane trafficking and signal transduction pathways.GRIP-GluA2/3 interactions are implicated in regulating AMPA-R synaptic targeting. Overexpression of the GluA2 C terminus in neurons decreases the synaptic targeting of AMPA-Rs (4). Point mutants of GluA2 that are unable to bind GRIP proteins exhibit reduced synaptic accumulation (20). GRIP1's sixth PDZ domain interacts with the α-liprin family of proteins, and disrupting GRIP-α-liprin interactions inhibits AMPA-R surface expression and synaptic targeting (14). GRIP proteins also bind ...

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Removal of AMPA Receptors (AMPARs) from Synapses Is Preceded by Transient Endocytosis of Extrasynaptic AMPARs

Cited by 225 publications

References 22 publications

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

Mechanisms Underlying Developmental Speeding in AMPA-EPSC Decay Time at the Calyx of Held

GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions

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