Moderate AMPA receptor clustering on the nanoscale can efficiently potentiate synaptic current

The prevailing view at present is that postsynaptic expression of the classical NMDA receptor-dependent long-term potentiation relies on an increase in the numbers of local AMPA receptors (AMPARs). This is thought to parallel an expansion of postsynaptic cell specializations, for instance dendritic spine heads, which accommodate synaptic receptor proteins. However, glutamate released into the synaptic cleft can normally activate only a hotspot of low-affinity AMPARs that occur in the vicinity of the release site. How the enlargement of the AMPAR pool is causally related to the potentiated AMPAR current remains therefore poorly understood. To understand possible scenarios of postsynaptic potentiation, here we explore a detailed Monte Carlo model of the typical small excitatory synapse. Simulations suggest that approximately 50% increase in the synaptic AMPAR current could be provided by expanding the existing AMPAR pool at the expense of 100–200% new AMPARs added at the same packing density. Alternatively, reducing the inter-receptor distances by only 30–35% could achieve a similar level of current potentiation without any changes in the receptor numbers. The NMDA receptor current also appears sensitive to the NMDA receptor crowding. Our observations provide a quantitative framework for understanding the ‘resource-efficient’ ways to enact use-dependent changes in the architecture of central synapses.

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Expression mechanisms underlying long-term potentiation: a postsynaptic view

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2002.1228 ◽

2003 ◽

Vol 358 (1432) ◽

pp. 721-726 ◽

Cited By ~ 126

Author(s):

Roger A. Nicoll

Keyword(s):

Nmda Receptor ◽

Ampa Receptors ◽

Glutamate Release ◽

Glutamate Transporter ◽

Long Term Potentiation ◽

Receptor Activation ◽

Covalent Modification ◽

Term Potentiation ◽

Expression Mechanism

This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particular N -methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.

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Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0136 ◽

2014 ◽

Vol 369 (1633) ◽

pp. 20130136 ◽

Cited By ~ 69

Author(s):

Adam J. Granger ◽

Roger A. Nicoll

Keyword(s):

Nmda Receptor ◽

Ampa Receptors ◽

Postsynaptic Density ◽

Long Term Potentiation ◽

The Past ◽

Reserve Pool ◽

Extrasynaptic Receptors ◽

Term Potentiation ◽

Expression Mechanism

This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.

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A Multisubcellular Compartment Model of AMPA Receptor Trafficking for Neuromodulation of Hebbian Synaptic Plasticity

Frontiers in Synaptic Neuroscience ◽

10.3389/fnsyn.2021.703621 ◽

2021 ◽

Vol 13 ◽

Author(s):

Stefan Mihalas ◽

Alvaro Ardiles ◽

Kaiwen He ◽

Adrian Palacios ◽

Alfredo Kirkwood

Keyword(s):

Synaptic Plasticity ◽

Ampa Receptors ◽

Compartment Model ◽

Long Term Potentiation ◽

Reverse Direction ◽

Term Potentiation ◽

Simple Kinetic Model ◽

Ampar Trafficking ◽

Central Synapses

Neuromodulation can profoundly impact the gain and polarity of postsynaptic changes in Hebbian synaptic plasticity. An emerging pattern observed in multiple central synapses is a pull–push type of control in which activation of receptors coupled to the G-protein Gs promote long-term potentiation (LTP) at the expense of long-term depression (LTD), whereas receptors coupled to Gq promote LTD at the expense of LTP. Notably, coactivation of both Gs- and Gq-coupled receptors enhances the gain of both LTP and LTD. To account for these observations, we propose a simple kinetic model in which AMPA receptors (AMPARs) are trafficked between multiple subcompartments in and around the postsynaptic spine. In the model AMPARs in the postsynaptic density compartment (PSD) are the primary contributors to synaptic conductance. During LTP induction, AMPARs are trafficked to the PSD primarily from a relatively small perisynaptic (peri-PSD) compartment. Gs-coupled receptors promote LTP by replenishing peri-PSD through increased AMPAR exocytosis from a pool of endocytic AMPAR. During LTD induction AMPARs are trafficked in the reverse direction, from the PSD to the peri-PSD compartment, and Gq-coupled receptors promote LTD by clearing the peri-PSD compartment through increased AMPAR endocytosis. We claim that the model not only captures essential features of the pull–push neuromodulation of synaptic plasticity, but it is also consistent with other actions of neuromodulators observed in slice experiments and is compatible with the current understanding of AMPAR trafficking.

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Sindbis viral-mediated expression of Ca2+-permeable AMPA receptors at hippocampal CA1 synapses and induction of NMDA receptor-independent long-term potentiation

European Journal of Neuroscience ◽

10.1046/j.0953-816x.2001.01523.x ◽

2001 ◽

Vol 13 (8) ◽

pp. 1635-1643 ◽

Cited By ~ 18

Author(s):

Takashi Okada ◽

Nobuaki Yamada ◽

Wataru Kakegawa ◽

Keisuke Tsuzuki ◽

Meiko Kawamura ◽

...

Keyword(s):

Nmda Receptor ◽

Ampa Receptors ◽

Long Term Potentiation ◽

Term Potentiation ◽

Hippocampal Ca1

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A selective LTP of NMDA receptor-mediated currents induced by anoxia in CA1 hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1993.70.5.2045 ◽

1993 ◽

Vol 70 (5) ◽

pp. 2045-2055 ◽

Cited By ~ 98

Author(s):

V. Crepel ◽

C. Hammond ◽

P. Chinestra ◽

D. Diabira ◽

Y. Ben-Ari

Keyword(s):

Nmda Receptor ◽

Ampa Receptor ◽

Ampa Receptors ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Peak Amplitude ◽

Excitatory Postsynaptic Potential ◽

Physiological Concentration ◽

Term Potentiation

1. The possibility of long-lasting modifications of glutamatergic responses after anoxic-aglycemic (AA) episodes was investigated in CA1 hippocampal neurons of adult slices. Bicuculline (10 microM) was continuously bath applied to block GABAA receptor-mediated currents. AA episodes were induced by brief (1.30-3 min) perfusions with a glucose free artificial-cerebro-spinal-fluid (ACSF) saturated with 95% N2-5% CO2. 2. In presence of (0.6 mM) Mg2+ and a low concentration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1 microM), the Schaffer collateral field EPSPs consisted of an early AMPA receptor-mediated component and a late N-methyl-D-aspartate (NMDA) receptor-mediated component. The former was blocked by (10 microM) CNQX and the latter by (50) microM D-2-amino-5-phosphonovalerate (D-APV). The AA episode induced a selective long-term potentiation (LTP) of the NMDA receptor-mediated component [+70 +/- 13% (mean +/- SE), P < or = 0.008, n = 9] without affecting significantly the AMPA receptor-mediated component (+2 +/- 4, P < or = 0.86 n = 9). This selective LTP is due to an enhanced efficacy of synaptic transmission and will be referred to as anoxic LTP. 3. In slices perfused with an ACSF containing a physiological concentration of (1.3 mM) Mg2+ and no CNQX, the intracellularly recorded excitatory postsynaptic potential (EPSP) was mixed (AMPA/NMDA) at -65 mV and exclusively mediated by AMPA receptors at -100 mV. At -65 mV, the AA episode induced a persistent potentiation of the EPSP (peak amplitude potentiated by 43 +/- 6%, P < or = 0.008, n = 9, 1 h after return to control ACSF). This potentiated component of the EPSP was fully sensitive to (50 microM) D-APV. The CNQX-sensitive AMPA receptor-mediated component was not affected by the AA episode (-5.7 +/- 6%, P < or = 0.123, n = 9). Furthermore, at -100 mV a large APV-sensitive component appeared after the AA episode (+58 +/- 18% of the peak amplitude, P < or = 0.018, n = 9). Therefore, the AA episode induced a selective LTP of the NMDA receptor-mediated component of the EPSP. 4. A robust LTP (+50.0 +/- 7.5%, P < or = 0.008, n = 12) of the NMDA receptor-mediated intracellular EPSP was also observed when AMPA receptors were fully and continuously blocked by (15 microM) CNQX.(ABSTRACT TRUNCATED AT 400 WORDS)

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Copper Inhibits NMDA Receptor-Independent LTP and Modulates the Paired-Pulse Ratio after LTP in Mouse Hippocampal Slices

International Journal of Alzheimer s Disease ◽

10.4061/2011/864753 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Nina L. Salazar-Weber ◽

Jeffrey P. Smith

Keyword(s):

Nmda Receptor ◽

Ampa Receptors ◽

Neurotransmitter Release ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Dependent Manner ◽

Paired Pulse ◽

Pulse Ratio ◽

Term Potentiation

Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release.

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