Hippocampal LTD Expression Involves a Pool of AMPARs Regulated by the NSF–GluR2 Interaction

Lüthi, Andreas; Chittajallu, Ramesh; Duprat, Fabrice; Palmer, Mary J.; Benke, Tim A.; Kidd, Fleur L.; Henley, Jeremy M.; Isaac, John T.R.; Collingridge, Graham L.

doi:10.1016/s0896-6273(00)80852-1

Cited by 267 publications

(232 citation statements)

References 33 publications

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“…As mentioned above, the hexameric chaperone NSF interacts directly with AMPA receptors, and disruption of this interaction causes a rapid loss of synaptic AMPA receptors (Nishimune et al, 1998;Osten et al, 1998;Song et al, 1998;Lüscher et al, 1999;Luthi et al, 1999;Noel et al, 1999;Shi et al, 2001). Therefore, our results indicate that both hsp90 and NSF are required for the rapid synaptic cycling of these receptors.…”

Section: Discussionsupporting

confidence: 65%

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Gerges¹,

Tran²,

Backos³

et al. 2004

J. Neurosci.

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The delivery of neurotransmitter receptors into synapses is essential for synaptic function and plasticity. In particular, AMPA-type glutamate receptors (AMPA receptors) reach excitatory synapses according to two distinct routes: a regulated pathway, which operates transiently during synaptic plasticity, and a constitutive pathway, which maintains synaptic function under conditions of basal transmission. However, the specific mechanisms that distinguish these two trafficking pathways are essentially unknown. Here, we evaluate the role of the molecular chaperone hsp90 (heat shock protein 90) in excitatory synaptic transmission in the hippocampus. On one hand, we found that hsp90 is necessary for the efficient neurotransmitter release at the presynaptic terminal. In addition, we identified hsp90 as a critical component of the cellular machinery that delivers AMPA receptors into the postsynaptic membrane. Using the hsp90-specific inhibitors radicicol and geldanamycin, we show that hsp90 is required for the constitutive trafficking of AMPA receptors into synapses during their continuous cycling between synaptic and nonsynaptic sites. In contrast, hsp90 function is not required for either the surface delivery of AMPA receptors into the nonsynaptic plasma membrane or for the acute, regulated delivery of AMPA receptors into synapses during plasticity induction (long-term potentiation). The synaptic cycling of AMPA receptors was also blocked by an hsp90-binding tetratricopeptide repeat (TPR) domain, suggesting that the role of hsp90 in AMPA receptor trafficking is mediated by a TPR domaincontaining protein. These results demonstrate new roles for hsp90 in synaptic function by controlling neurotransmitter release and, independently, by mediating the continuous cycling of synaptic AMPA receptors.

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Section: Discussionsupporting

confidence: 65%

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Gerges¹,

Tran²,

Backos³

et al. 2004

J. Neurosci.

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“…To date, studies of AMPA receptor trafficking have focused on the presence or absence of AMPA receptors at synaptic sites, or on internal versus surface expression [3][4][5][6][7][8][9][10][15][16][17][18] . However, the multiple subunits of AMPA receptors interact differentially with diverse cytoplasmic proteins including GRIP/ABP, PICK1, NSF and SAP97, all of which have been implicated in synaptic targeting of AMPA receptors 3,5,17,[19][20][21][22][23][24][25][26][27] .…”

Section: Articlesmentioning

confidence: 99%

Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization

et al. 2000

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articlesThe AMPA class of ionotropic glutamate receptors mediates most of the fast excitatory synaptic transmission in mammalian brain 1 . Changing the responsiveness of postsynaptic AMPA receptors offers a powerful way to regulate excitatory synaptic transmission. Among the mechanisms proposed for modification of AMPA receptor activity, one of the simplest is a change in the number of AMPA receptors in the postsynaptic membrane. Studies suggest that AMPA receptors can move in and out of the postsynaptic membrane on a rapid time scale (for review, see ref.2). Moreover, changes in postsynaptic membrane trafficking or in synaptic targeting of AMPA receptors have been correlated with alterations in synaptic efficacy [2][3][4][5][6][7][8][9] .In developing neurons in culture, synaptic expression of AMPA receptors is modulated over a period of days by relative levels of AMPA and NMDA receptor activity [10][11][12] . Mature neurons in culture also exhibit slow changes in synaptic AMPA receptor expression in response to chronic changes in endogenous activity 9,13,14 . On a faster time scale, induction of long-term depression (LTD) or acute application of AMPA or insulin can induce a loss of AMPA receptors from the cell surface of cultured hippocampal neurons within minutes 3,6,9,15 . Conversely, induction of long-term potentiation (LTP) and activation of CaMKII are correlated with a rapid recruitment of AMPA receptors to the postsynaptic membrane 5,8 . Thus, the synaptic content of AMPA receptors can change bidirectionally on a fast time scale and result in altered synaptic transmission.Little is known about the cell biological pathways or molecular mechanisms of postsynaptic AMPA receptor trafficking. To date, studies of AMPA receptor trafficking have focused on the presence or absence of AMPA receptors at synaptic sites, or on internal versus surface expression [3][4][5][6][7][8][9][10][15][16][17][18] . However, the multiple subunits of AMPA receptors interact differentially with diverse cytoplasmic proteins including GRIP/ABP, PICK1, NSF and SAP97, all of which have been implicated in synaptic targeting of AMPA receptors 3,5,17,[19][20][21][22][23][24][25][26][27] . The diversity of AMPA receptor protein interactions, and their regulation by phosphorylation 28 , suggest that AMPA receptor trafficking is likely to be regulated by varied mechanisms.Here we report that multiple distinct pathways exist for AMPA receptor endocytosis in cultured hippocampal neurons. We have quantified a basal rate of AMPA receptor internalization, which can be enhanced by a variety of stimuli including synaptic activity, ligand binding to AMPA receptors, insulin and calcium influx. Different internalizing stimuli use distinct intracellular signaling mechanisms, different endosomal sorting pathways and distinct sequence determinants within AMPA receptor subunits to effect AMPA receptor endocytosis. RESULTS Ligand-dependent endocytosis of AMPA receptorsTranslocation of AMPA receptors from cell surface to intracellular compartments was visu...

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“…12 ). Furthermore, disrupting the NSF-GluR2 interaction also occluded LTD (Refs 12,50 ). However, LTD is also blocked by peptides that prevent the interaction between GluR2 and PDZ domains (see above), even though these peptides only have sporadic effects on baseline transmission.…”

Section: Ltdmentioning

confidence: 99%

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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Hippocampal LTD Expression Involves a Pool of AMPARs Regulated by the NSF–GluR2 Interaction

Cited by 267 publications

References 33 publications

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization

Restless AMPA receptors: implications for synaptic transmission and plasticity

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