Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures

Rc, Carroll; Dv, Lissin; M, von Zastrow; Nicoll, RA; Malenka, RC

doi:10.1038/8123

Cited by 415 publications

(296 citation statements)

References 49 publications

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“…12 ). In cultured hippocampal neurons, where changes in the synaptic AMPARs can be directly visualized, LTD induction led to decreases in synaptic efficacy that were associated with a loss of synaptic GluR1 puncta but not NMDAR1 puncta 49 . The pool of AMPARs internalized by LTD appears to overlap to a large extent with the constitutively recycling pool, as the rundown of EPSCs in the presence of botulinum toxin occludes subsequent LTD (Ref.…”

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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Section: Ltdmentioning

confidence: 99%

Restless AMPA receptors: implications for synaptic transmission and plasticity

Lüscher

Frerking

2001

Trends in Neurosciences

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“…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] .…”

Section: Articlesmentioning

confidence: 99%

“…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 .…”

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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“…Most studied in this respect are the actions of CNS glutamatergic receptors that participate in numerous signal transduction and regulatory events. Prominent examples include forms of synaptic plasticity involving a rapid redistribution of AMPA receptors on the cell surface as well as transfer between surface and intracellular locations (Nishimune et al, 1998;Osten et al, 1998;Carroll et al, 1999;Luscher et al, 1999;Hayashi et al, 2000;Hanley et al, 2002). NMDA receptors undergo several other forms of calcium-controlled regulation including activity-dependent inactivation and rundown (Legendre et al, 1993;Westbrook, 1993a, 1993b;Westbrook et al, 1997;Wyszynski et al, 1997;Zhang et al, 1998;Krupp et al, 1999).…”

Section: Short-term Consequencesmentioning

confidence: 99%

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

2002

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Nicotinic receptors are cation-ion selective ligand-gated ion channels that are expressed throughout the nervous system. Most have significant calcium permeabilities, enabling them to regulate calcium-dependent events. One of the most abundant is a species composed of the ␣7 gene product and having a relative calcium permeability equivalent to that of NMDA receptors. The ␣7-containing receptors can be found presynaptically where they modulate transmitter release, and postsynaptically where they generate excitatory responses. They can also be found in perisynaptic locations where they modulate other inputs to the neuron and can activate a variety of downstream signaling pathways. The effects the receptors produce depend critically on the sites at which they are clustered. Instructive preparations for examining ␣7-containing receptors are the rat hippocampus, where they are thought to play a modulatory role, and the chick ciliary ganglion, where they participate in throughput transmission as well as regulatory signaling. Relatively high levels of ␣7-containing receptors are found in the two preparations, and the receptors display a variety of synaptic options and functions in the two cases. Progress is starting to be made in understanding the mechanisms responsible for localizing the receptors at specific sites and in identifying components tethered in the vicinity of the receptors that may facilitate signal transduction and downstream signaling.

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Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures

Cited by 415 publications

References 49 publications

Restless AMPA receptors: implications for synaptic transmission and plasticity

Restless AMPA receptors: implications for synaptic transmission and plasticity

Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

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