Postsynaptic Membrane Fusion and Long-Term Potentiation

Lledo, Pierre−Marie; Zhang, Xiangyang; Südhof, Thomas C.; Malenka, Robert C.; Nicoll, Roger A.

doi:10.1126/science.279.5349.399

Cited by 386 publications

(313 citation statements)

References 33 publications

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“…Activity-dependent recruitment of AMPARs is well described (Liao et al, 2001;O'Brien et al, 1998;Turrigiano, 2000) and is a final common pathway mediating activity-dependent changes in synaptic efficacy at CA1 excitatory synapses both in vivo and in vitro (Baudry and Lynch, 2001;Liao et al, 1995;Lledo et al, 1998;Nayak et al, 1998;Zamanillo et al, 1999). Activitydependent changes in synaptic function are primarily the consequence of intracellular Ca 2 þ -dependent biochemical cascades and involve changes in synaptic AMPAR number and/or function (Hayashi et al, 2000;Song and Huganir, 2002).…”

Section: Discussionmentioning

confidence: 98%

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Sickle

Kong

Tietz

2004

Neuropsychopharmacol

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Withdrawal from 1-week oral administration of the benzodiazepine (BZ), flurazepam (FZP) is associated with enhanced AMPA receptor (AMPAR)-mediated and reduced NMDA receptor (NMDAR)-mediated excitation in CA1 pyramidal neurons 2-days after cessation of FZP administration. The present study examined temporal regulation of glutamate receptor-mediated whole-cell currents in CA1 neurons from hippocampal slices prepared from 0-, 1-, 2-, and 4-day FZP-withdrawn rats in relation to expression of anxiety-like behavior during BZ withdrawal. AMPAR-mediated miniature excitatory postsynaptic current (mEPSC) amplitude was significantly increased in CA1 neurons from 1-and 2-day FZP-withdrawn rats, while evoked NMDAR EPSC amplitude was reduced only in neurons from 2-day FZP-withdrawn rats. Withdrawal-anxiety, measured in the elevated plus-maze, was observed 1 day, but not 0, 2, or 4 days, after FZP treatment with 1-day withdrawn rats spending significantly reduced time in open arms compared to controls. CA1 neuron hyperexcitability was evident from the significant increase in the frequency of extracellular, 4-AP-induced spike discharges in slices from 1-day FZP-withdrawn rats. Systemic injection of the NMDAR antagonist MK-801 (0.25 mg/kg) on day 1 of withdrawal prevented reduced NMDAR-mediated currents in CA1 neurons from 2-day FZP-withdrawn rats, whereas AMPAR-mediated currents remained upregulated. Furthermore, MK-801 'unmasked' withdrawal-anxiety in the same 2-day FZP-withdrawn rats. Systemic injection of the AMPAR antagonist GYKI-52466 (0.5 mg/kg) at the onset of withdrawal blocked increased AMPAR-mediated currents and withdrawal-anxiety in 1-day FZP-withdrawn rats. These findings suggest that increased CA1 neuron AMPAR-mediated excitation may contribute to hippocampal hyperexcitability and expression of withdrawal-anxiety after prolonged BZ exposure via NMDAR-mediated neural circuits.

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Section: Discussionmentioning

confidence: 98%

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Sickle

Kong

Tietz

2004

Neuropsychopharmacol

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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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“…Both of these models predict exocytosis would be essential for LTP. Indeed cleavage of postsynaptic v-SNAREs by introducing either botulinum toxin or tetanus toxin into CA1 neurons prevented LTP expression 15 . In these experiments, the effects of these toxins on constitutive cycling were not observed.…”

Section: Do Ampars Move During Synaptic Plasticity? Ltpmentioning

confidence: 99%

“…15 ), synaptobrevin 12 and N-ethylmaleimide-sensitive fusion protein (NSF) 12,[16][17][18] . An intriguing, but poorly understood, aspect of exocytosis is that GluR2 has been shown to specifically interact with NSF (see Table 1), which is enriched in the postsynaptic density (PSD) (for reviews see Refs 19,20 ).…”

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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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Postsynaptic Membrane Fusion and Long-Term Potentiation

Cited by 386 publications

References 33 publications

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Transient Plasticity of Hippocampal CA1 Neuron Glutamate Receptors Contributes to Benzodiazepine Withdrawal-Anxiety

Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization

Restless AMPA receptors: implications for synaptic transmission and plasticity

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