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Cited by 1,110Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsTreatment of Major Depression

NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD).

Open access
Luscher, C., Malenka, R. C.·2012·Cold Spring Harbor Perspectives in Biology
DOI 10.1101/cshperspect.a005710PMC PMC3367554
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Abstract

Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory.

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a005710

Cites

95 of 95 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

18 of 124 cited sources checked · 10 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The insertion and removal of AMPARs during LTP and LTD, respectively, is believed to involve classical mechanisms of SNARE protein-mediated exocytosis and dynamin-dependent endocytosis via clathrin-coated vesicles.

    “The insertion and removal of AMPARs during LTP and LTD, respectively, is believed to involve classical mechanisms of SNARE protein -mediated exocytosis and dynamin-dependent endocytosis via clathrin-coated vesicles (Lu ¨scher et al. 1999;Carroll et al. 2001;Kennedy and Ehlers 2011).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Lu ¨scher et al. 1999

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Carroll et al. 2001 source
    • cites Kennedy and Ehlers 2011 source

      The section “Postsynaptic Exocytosis and Synaptic Plasticity” describes SNARE-mediated postsynaptic fusion as a mechanism implicated in AMPA-receptor insertion during LTP. Our copy does not substantiate the other half of the claim: AMPA-receptor removal during LTD by dynamin-dependent endocytosis through clathrin-coated vesicles. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    CaMKII activation leads to the phosphorylation of a number of proteins including AMPARs themselves.

    “This leads to the phosphorylation of a number of proteins including AMPARs themselves (Derkach et al. 1999).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Derkach et al. 1999 source

      The Results report that activated CaMKII greatly enhances phosphorylation of the AMPAR subunit GluR1 at Ser-831, and the Discussion identifies CaMKII-mediated phosphorylation of AMPARs. These passages support the AMPAR part of the claim, but do not establish that CaMKII phosphorylates a number of other proteins. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    Interactions between neighboring synapses do occur, such that intradendritic spread of activated Ras from an active synapse briefly lowers the threshold for subsequent LTP induction at neighboring synapses.

    “However, interactions between neighboring synapses do occur, such that the intradendritic spread of the activated Ras from an active synapse briefly lowers the threshold for subsequent LTP induction at neighboring synapses (Harvey et al. 2008).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Harvey et al. 2008 source
  • Premisecitation

    LTP can be induced at a single synapse without causing postsynaptic potentiation or depression of neighboring synapses.

    “Experiments using this approach to induce NMDAR-dependent LTP have shown that LTP can be induced at a single synapse without causing postsynaptic potentiation or depression of neighboring synapses (Matsuzaki et al. 2004;Harvey and Svoboda 2007; but see Engert and Bonhoeffer 1997).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Matsuzaki et al. 2004 source
    • cites Harvey and Svoboda 2007 source
    • cites Engert and Bonhoeffer 1997 source
  • Premisecitation

    Heteromeric GluA1/GluA2 receptors seem to be the primary subtype of AMPAR that is inserted into synapses during LTP.

    “Heteromeric GluA1/GluA2 receptors seem to be the primary subtype of AMPAR that is inserted into synapses during LTP (Adesnik and Nicoll 2007).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Adesnik and Nicoll 2007 source

      The Discussion concludes that LTP in CA1 does not involve insertion of calcium-permeable AMPARs, supporting a role for GluA2-containing receptors. But the paper does not identify the inserted receptors specifically as GluA1/GluA2 heteromers or establish that they are the primary subtype across synapses generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    Spine density increases following LTP induction, and a significantly higher frequency of multiple-spine synapses is observed, as well as a reduction of their turnover.

    “Consistent with this idea, the spine density increases following LTP induction, and a significantly higher frequency of multiple-spine synapses (Toni et al. 1999) is observed, as well as a reduction of their turnover (De Roo et al. 2008).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Toni et al. 1999 source
    • cites De Roo et al. 2008 source

      The De Roo citation is attached to the claimed reduction in turnover. The Results section, “LTP Induction Results in a Lasting Increase in Protrusion Turnover” (page unavailable), reports that turnover increased for several days after LTP induction; the Discussion likewise calls it a lasting, enhanced turnover. The paper does report selective stabilization of stimulated spines, but not an overall reduction in turnover. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Consistent with original ideas, modest depolarization can elicit LTD, whereas stronger depolarization leads to LTP.

    “Consistent with original ideas (Bienenstock et al. 1982), modest depolarization can elicit LTD, whereas stronger depolarization leads to LTP.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bienenstock et al. 1982 source

      Section II, “Modification of Cortical Synapses” (page unavailable), proposes that synaptic strength decreases when postsynaptic output is below a modification threshold and increases when it is above it. This supports the claim’s low-versus-high activity pattern, but the paper describes a theoretical rule based on postsynaptic response, not a finding that modest versus stronger depolarization elicits LTD and LTP. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The driving force for calcium entry is very large for a neuron at rest and the block of NMDARs by Mg2+ is incomplete even at resting potentials, so significant Ca enters the cell in response to synaptic stimulation during low-frequency synaptic stimulation.

    “Because the driving force for calcium entry is very large for a neuron at rest and the block of NMDARs by Mg 2þ is incomplete even at resting potentials (Jahr and Stevens 1993), significant Ca enters the cell in response to synaptic stimulation (Sabatini et al. 2002;Bloodgood and Sabatini 2007;Bloodgood et al. 2009) during low-frequency synaptic stimulation.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Jahr and Stevens 1993 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites Sabatini et al. 2002 source
    • cites Bloodgood and Sabatini 2007 source

  • May combine two claims.

    Premisecitation

    Early drug-evoked changes in the properties of excitatory synapses on dopamine cells can be very long-lasting and are followed by many additional synaptic modifications in related structures.

    “These early drug-evoked changes in the properties of excitatory synapses on dopamine cells can be very long-lasting and are followed by many additional synaptic modifications in related structures.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Thomas and Malenka 2003 source
    • cites Kauer and Malenka 2007 source
    • cites Wolf and Ferrario 2010 source

      Section 5.3 (page unavailable) reports that early plasticity in VTA dopamine neurons is required for subsequent changes in nucleus accumbens AMPAR transmission, and discusses later adaptations in other VTA targets. It does not establish that the early synaptic changes themselves are very long-lasting; the changes it says persist after long withdrawal are in the nucleus accumbens. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationreasoning

    NMDARs act as molecular coincidence detectors, which is essential for several forms of synaptic plasticity.

    “Through this mechanism NMDARs play the role of molecular coincidence detectors, which, as we will see below, is essential for several forms of synaptic plasticity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The AMPAR is the workhorse of glutamatergic transmission and drives large and rapid synaptic signaling.

    “The workhorse of glutamatergic transmission is the AMPAR, which drives large and rapid synaptic signaling (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NMDARs and AMPARs are ionotropic receptors that are permeable to Na+ and K+.

    “Both are ionotropic receptors that are permeable to Na þ and K þ .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dingledine et al. 1999 source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    At CA3-CA1 Schaffer collateral synapses, the loci of both induction and expression are situated in the postsynaptic neuron.

    “At these CA3-CA1 Schaffer collateral synapses, the loci of both induction and expression are situated in the postsynaptic neuron.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The early phases of LTP/LTD expression are mediated by redistribution of AMPA-type glutamate receptors, with more receptors added to potentiate synapses and receptors removed to weaken synapses.

    “The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses.”
    • Also stated in: § EXPRESSION MECHANISM · boosted
      “A large body of experimental evidence now supports this hypothesis (Lu ¨scher et al. 2000;Lu ¨scher and Frerking 2001;Malinow and Malenka 2002;Nicoll 2003;Collingridge et al. 2004;Malenka and Bear 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lledo et al. 1998 source
    • cites Lu ¨scher et al. 1999

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Activation of ionotropic glutamate receptors leads to strong influx of Na+ and only a small efflux of K+, such that the net effect is depolarization of the postsynaptic neuron.

    “Activation of ionotropic glutamate receptors leads to strong influx of Na þ and only a small efflux of K þ , such that the net effect is the depolarization of the postsynaptic neuron.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some postsynaptic density proteins modulate glutamate receptor function, whereas others control their membrane insertion and removal.

    “Some of these proteins modulate glutamate receptor function, whereas others control their membrane insertion and removal.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Elias and Nicoll 2007 source

  • May combine two claims.

    Premisecitation

    For LTP there is strong evidence that the opening of NMDARs increases calcium concentration sufficiently in the dendritic spine to activate CaMKII, which is found at very high concentrations in spines and is clearly required for LTP.

    “For LTP there is strong evidence that the opening of NMDARs increases calcium concentration sufficiently in the dendritic spine to activate calcium/calmodulin-dependent kinase II (CaMKII), which is found at very high concentrations in spines and which is clearly required for LTP (Lisman et al. 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lisman et al. 2002 source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Because GluA2-lacking AMPARs have a higher conductance, exchanging them for GluA2-containing AMPARs will potentiate the synapse even if the total number remains the same.

    “Because the latter have a higher conductance, this will potentiate the synapse even if the total number remains the same.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    High-frequency stimulation protocols cause strong temporal summation of EPSPs, and the resultant large depolarization of the postsynaptic cell is sufficient to relieve the Mg2+ block of NMDARs and allow a large amount of calcium to enter during induction.

    “However, this makes sense because high-frequency stimulation protocols cause a strong temporal summation of the excitatory postsynaptic potentials (EPSPs), and the resultant large depolarization of the postsynaptic cell is sufficient to relieve the Mg block of the NMDAR and allow a large amount of calcium to enter the postsynaptic cells during the induction protocol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Modest activation of NMDARs leading to modest increases in postsynaptic calcium is optimal for triggering LTD, whereas much stronger activation leading to much larger increases in postsynaptic calcium is required to trigger LTP.

    “Indeed, it is now fairly well accepted that modest activation of NMDARs leading to modest increases in postsynaptic calcium are optimal for triggering LTD, whereas much stronger activation of NMDARs leading to much larger increases in postsynaptic calcium are required to trigger LTP (Malenka 1994).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Malenka 1994 source

  • May combine two claims.

    Interpretationcitation

    From the postsynaptic neuron perspective, these manipulations lead to both a synaptic potential and an action potential that backpropagates into dendrites, which presumably provides additional depolarization required to facilitate calcium influx through activated NMDARs.

    “From the perspective of the postsynaptic neuron (which is where the recordings are made), these manipulations lead to both a synaptic potential and an action potential that backpropagates into the dendrites, which presumably provides the additional depolarization required to facilitate calcium influx through the activated NMDARs (Stuart et al. 1997;Waters et al. 2005).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Stuart et al. 1997 source
    • cites Waters et al. 2005 source

  • May combine two claims.

    Premisereasoning

    For LTP induction, both pre- and postsynaptic neurons need to be active at the same time because the postsynaptic neuron must be depolarized when glutamate is released to fully relieve the Mg2+ block of NMDARs.

    “For LTP induction both pre-and postsynaptic neurons need to be active at the same time because the postsynaptic neuron must be depolarized when glutamate is released from the presynaptic bouton to fully relieve the Mg 2þ block of NMDARs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Paired-pulse ratios and short-term facilitation or depression of synaptic responses during short, high-frequency bursts are greatly influenced by baseline release probability yet were unaffected by the generation of LTP.

    “These ubiquitous forms of short-term synaptic plasticity are greatly influenced by the baseline release probability yet were unaffected by the generation of LTP (McNaughton 1982;Manabe et al. 1993; but see Schulz et al. 1995).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites McNaughton 1982 source
    • cites Manabe et al. 1993 source
    • cites Schulz et al. 1995 source

  • May combine two claims.

    Interpretationreasoning

    NMDAR-dependent LTP is an associative form of plasticity and fulfills the criteria for correlated activity as the origin of strengthening of the connection between two neurons proposed by Donald Hebb.

    “NMDAR-dependent LTP is therefore an associative form of plasticity and fulfills the criteria for correlated activity as the origin of the strengthening of the connection between two neurons proposed by Donald Hebb more than 60 years ago (Hebb 1949).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hebb 1949

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    There is no change in the size of glial glutamate transporter currents after induction of LTP even though other manipulations that affect transmitter release have clear effects.

    “There is, however, no change in the size of these currents after induction of LTP even though other manipulations that affect transmitter release have clear effects.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Diamond et al. 1998 source
    • cites Lu ¨scher et al. 1998

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Members of the TARP family interact with all AMPA receptor subunits and control not only membrane insertion but also lateral redistribution.

    “Of particular interest are members of the TARP family, which interact with all AMPA receptor subunits and control not only membrane insertion but also lateral redistribution (Chen et al. 2000;Tomita et al. 2005; see Blakely and Edwards 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chen et al. 2000 source
    • cites Tomita et al. 2005 source
    • cites Blakely and Edwards 2012 source

  • May combine two claims.

    Interpretationreasoning

    Coincident depolarization and glutamate binding causes maximal calcium influx through NMDARs, which activates intracellular signaling cascades responsible for altered synaptic efficacy.

    “As a consequence of coincident depolarization and glutamate binding, calcium influx through NMDARs is maximal, which activates intracellular signaling cascades that ultimately are responsible for the altered synaptic efficacy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    As the direction of synaptic plasticity depends on the timing between presynaptic and postsynaptic spikes, this phenomenon is named spike-timing-dependent plasticity.

    “As the direction of synaptic plasticity depends on the timing between the presynaptic and postsynaptic spikes, this phenomenon has been named spike-timing-dependent plasticity (Dan and Poo 2006;Caporale and Dan 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dan and Poo 2006 source
    • cites Caporale and Dan 2008 source

  • May combine two claims.

    Interpretationreasoning

    Low-frequency stimulation of presynaptic axons causes only a modest amount of postsynaptic depolarization, resulting in a modest but prolonged increase in postsynaptic calcium due to modest and repetitive activation of NMDARs.

    “This causes only a modest amount of postsynaptic depolarization, resulting in a modest but prolonged increase in postsynaptic calcium due to modest and repetitive activation of NMDARs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Appropriate coincident activity of the pre- and postsynaptic neurons causes an influx of calcium through NMDARs, and depending on the quantitative characteristics of this calcium signal, AMPARs are either inserted into or removed from the synapses, resulting in LTP or LTD.

    “Appropriate coincident activity of the pre-and postsynaptic neurons causes an influx of calcium through NMDARs, and depending on the quantitative characteristics of this calcium signal, AMPARs are either inserted into or removed from the synapses, resulting in LTP or LTD, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The rate of decrease of NMDAR currents during MK-801 application remains unaltered by LTP but is clearly affected by other manipulations that are known to influence the probability of transmitter release.

    “Importantly, it was found that the rate of this decrease remains unaltered by LTP but is clearly affected by other manipulations that are known to influence the probability of transmitter release (Manabe and Nicoll 1994).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Manabe and Nicoll 1994 source

  • May combine two claims.

    Interpretationreasoning

    At both silent synapses and synapses that already contain AMPARs, LTP involves the insertion of more AMPARs into the synapse, whereas LTD involves the removal or endocytosis of synaptic AMPARs.

    “This result immediately raised the possibility that at both silent synapses and synapses that already contain AMPARs, LTP involves the insertion of more AMPARs into the synapse, whereas conversely, LTD may involve the removal or endocytosis of synaptic AMPARs (Fig. 3) (Lledo et al. 1998;Lu ¨scher et al. 1999).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lledo et al. 1998 source
    • cites Lu ¨scher et al. 1999

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Toxic Ab decreases synaptic NMDARs, a change that contributes to the impaired LTP.

    “Furthermore, the toxic Ab also decreases synaptic NMDARs, a change that contributes to the impaired LTP (Kamenetz et al. 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kamenetz et al. 2003 source

  • May combine two claims.

    Premisecitation

    BDNF-dependent I-LTP is induced by activation of NMDARs (and sometimes voltage-gated calcium channels) and modulated by GABA B receptors, which together drive an increase in cytoplasmic calcium, in part by triggering the release of calcium from intracellular stores.

    “It is induced by activation of NMDARs (and sometimes voltagegated calcium channels) and modulated by GABA B receptors, which together drive an increase in cytoplasmic calcium, in part by triggering the release of calcium from intracellular stores.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Inagaki et al. 2008 source

  • May combine two claims.

    Premisecitation

    Such perforated synapses also contain a higher proportion of smooth endoplasmic reticulum and a spine apparatus.

    “Such perforated synapses also contain a higher proportion of smooth endoplasmic reticulum and a spine apparatus (Lu ¨scher et al. 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lu ¨scher et al. 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Perfusing postsynaptic neurons with activated CaMKII occludes further LTP, suggesting a shared mechanism between the ways of increasing synaptic strength.

    “Importantly, this manipulation occludes further LTP, suggesting a shared mechanism between the ways of increasing synaptic strength (Malenka and Nicoll 1999;Lisman et al. 2002).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Malenka and Nicoll 1999 source
    • cites Lisman et al. 2002 source

  • May combine two claims.

    Premisecitation

    The increase of this IPSP depends on NMDAR activation and CaMKII, sharing two key properties with hippocampal LTP of AMPARs.

    “The increase of this IPSP also depends on NMDAR activation and CaMKII, thus sharing two key properties with hippocampal LTP of AMPARs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huang et al. 2005 source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Calcineurin has a much higher affinity for calcium/calmodulin than does CaMKII and thus will be preferentially activated by a modest increase in calcium, the exact trigger for LTD.

    “This is a very attractive model because calcineurin has a much higher affinity for calcium/calmodulin than does CaMKII and thus will be preferentially activated by a modest increase in calcium, the exact trigger for LTD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Synaptic plasticity of GABAergic transmission needs the activation of glutamatergic synapses and a specific messenger that passes the signal from one type of synapses to the other.

    “Synaptic plasticity of GABAergic transmission needs the activation of glutamatergic synapses and a specific messenger that passes the signal from one type of synapses to the other.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In this model, NMDAR activation leads to postsynaptic release of BDNF, which functions as a retrograde messenger and causes an increase in GABA release through activation of presynaptic TrkB receptors.

    “In this model NMDAR activation leads to postsynaptic release of BDNF, which functions as a retrograde messenger and causes an increase in GABA release through activation of presynaptic TrkB receptors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Inagaki et al. 2008 source

  • May combine two claims.

    Premisecitation

    NMDAR-dependent LTD depends on the calcium/calmodulin-dependent protein phosphatase calcineurin as well as on protein phosphatase 1 (PP1).

    “Indeed, a very influential model proposed that NMDAR-dependent LTD depends on the calcium/calmodulin-dependent protein phosphatase calcineurin as well as on protein phosphatase 1 (PP1) (Lisman 1989).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lisman 1989 source

  • May combine two claims.

    Premisecitation

    LTP GABA induction leads to activation of a Ca2+-dependent nitric oxide synthase, which generates nitric oxide, which acts as a retrograde messenger by diffusing back to presynaptic neurons.

    “This leads to activation of a Ca 2þ -dependent nitric oxide synthase, which generates nitric oxide, which acts as a retrograde messenger by diffusing back to presynaptic neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nugent et al. 2007 source

  • May combine two claims.

    Interpretationreasoning

    LTP may guide the selective stabilization of synaptic inputs that show coincident activity, whereas nonactivated inputs may be removed and replaced by new spines.

    “Through these mechanisms LTP may guide the selective stabilization of synaptic inputs that show coincident activity, whereas nonactivated inputs may be removed and replaced by new spines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premiseown data

    Direct application or overproduction of Ab oligomers both inhibits LTP and triggers LTD-like changes.

    “Direct application or overproduction of Ab oligomers both inhibits LTP and triggers LTD-like changes (Fig. 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 5

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Soluble Ab oligomers strongly activate metabotropic glutamate receptors (mGluRs), which leads to the internalization of AMPARs and LTD.

    “Soluble Ab oligomers strongly activate metabotropic glutamate receptors (mGluRs), which leads to the internalization of AMPARs and LTD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 5

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    This drug-evoked plasticity requires activation of type 1 dopamine receptors along with NMDAR activation and is expressed by a redistribution of AMPARs and NMDARs.

    “This drug-evoked plasticity requires activation of type 1 dopamine receptors along with NMDAR activation and is expressed by a redistribution of AMPARs and NMDARs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ungless et al. 2001 source

  • May combine two claims.

    Premisereasoning

    In a second step, synapses become thinner and some disappear in AD.

    “In a second step synapses become thinner and some disappear.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 5

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisenone given

    AMPA receptors have a linear I-V relationship when they contain the subunit GluA2, but are inward-rectifying without GluA2.

    “AMPA receptors have a linear I -V relationship when they contain the subunit GluA2, but are inward-rectifying (see text for definition) without GluA2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fig. 2

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premiseown data

    Soluble Ab oligomers inhibit NMDARs, precluding the induction of LTP.

    “At the same time they inhibit NMDARs, precluding the induction of LTP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 5

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

44 of 44

  • The paper relies on this without support.

    NMDAR-dependent LTP and LTD are cellular substrates or correlates of learning and memory.

    “The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory.”
    “Because both LTP and LTD are believed to represent cellular correlates of learning and memory, they have attracted considerable interest.”

  • The paper relies on this without support.

    NMDAR-dependent LTP and LTD are triggered in the postsynaptic cell.

    “This is re-quired because it is well established that NMDAR-dependent LTP and LTD are triggered in the postsynaptic cell.”

  • The paper relies on this without support.

    Altered LTP and LTD contributes to the pathophysiology of brain diseases such as dementia, movement disorders, depression, addiction, posttraumatic stress syndrome, neuropathic pain, and anxiety disorders.

    “Altered LTP and LTD has been implicated as a mechanism that may contribute to brain diseases as diverse as dementia, movement disor-ders, depression, addiction, posttraumatic stress syndrome, neuropathic pain, and anxiety disorders.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Decreased A/N ratios of M1/M2-to-DLS synapses indicate decreased synaptic strength.

    “The decreased A/N ratios of M1/M2-to-DLS synapses indicate decreased synaptic strength, since typically it is the number of functional AMPAR, not NMDAR, that changes in the synaptic composition when synapses modify their strength [23].”

    From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [23]

  • Typically, the number of functional AMPAR, not NMDAR, changes in synaptic composition when synapses modify their strength.

    “The decreased A/N ratios of M1/M2-to-DLS synapses indicate decreased synaptic strength, since typically it is the number of functional AMPAR, not NMDAR, that changes in the synaptic composition when synapses modify their strength [23].”

    From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [23]

  • Defects in enhancer decommissioning might contribute to synaptic plasticity defects in neuropsychiatric diseases.

    “the colocalization of schizophrenia-associated SNVs with class 3 loops suggests that defects in enhancer decommissioning might contribute to synaptic plasticity defects in neuropsychiatric diseases47.”

    From Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression (2020) · cites this paper as [47]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conclusion requires postsynaptic activity for LTD despite an earlier counterexample

    Minor

    The conclusion says coincident pre- and postsynaptic activity is necessary to trigger both LTP and LTD. Earlier, the paper says LTD can be induced without postsynaptic activity.

  • LTD is described as increasing synaptic strength

    Minor

    The maintenance section refers to an increase in synaptic strength accompanying LTD, whereas the abstract describes LTD-related receptor removal as weakening synapses.

2 of 2

Cites

Flagged first, then by citations

4 of the 99 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Luscher, C., & Malenka, R. C.
Affiliations
Stanford Medicine (US)
ORCID
Malenka, R. C.
Venue
Cold Spring Harbor Perspectives in Biology
Publisher
Cold Spring Harbor Laboratory
Published
2012-04-17
Volume
4
Issue
6
Pages
a005710-a005710
ISSN
1943-0264 (ISSN-L)
DOI
10.1101/cshperspect.a005710
PMC
PMC3367554
OpenAlex
W2137841176
Cited by
1,110
References
99
Citations by year
2026: 72 · 2025: 119 · 2024: 128 · 2023: 87 · 2022: 76 · 2021: 107 · 2020: 101 · 2019: 95 · 2018: 98 · 2017: 75 · 2016: 56 · 2015: 37 · 2014: 30 · 2013: 22 · 2012: 5
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
NMDA receptor, long-term potentiation, long-term depression, synaptic plasticity, learning and memory, protein synthesis
MeSH terms
Humans, Learning, Memory, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Long-Term Synaptic Depression

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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