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Cited by 126Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsProtein Kinase Regulation and GTPase Signaling

Synaptic memory and CaMKII

Open access
Nicoll, Roger A., Schulman, Howard·2023·Physiological Reviews
DOI 10.1152/physrev.00034.2022PMC PMC10642921
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Abstract

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other and have been inextricably intertwined ever since. However, like many marriages, it has had its up and downs. Based on the unique biochemical properties of CaMKII, it was proposed as a memory molecule before any physiological linkage was made to LTP. However, as reviewed here, the convincing linkage of CaMKII to synaptic physiology and behavior took many decades. New technologies were critical in this journey, including in vitro brain slices, mouse genetics, single-cell molecular genetics, pharmacological reagents, protein structure, and two-photon microscopy, as were new investigators attracted by the exciting challenge. This review tracks this journey and assesses the state of this marriage 40 years on. The collective literature impels us to propose a relatively simple model for synaptic memory involving the following steps that drive the process: 1) Ca 2+ entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) CaMKII undergoes autophosphorylation resulting in constitutive, Ca 2+ -independent activity and exposure of a binding site for the NMDA receptor subunit GluN2B. 3) Active CaMKII translocates to the postsynaptic density (PSD) and binds to the cytoplasmic C-tail of GluN2B. 4) The CaMKII-GluN2B complex initiates a structural rearrangement of the PSD that may involve liquid-liquid phase separation. 5) This rearrangement involves the PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and their transmembrane AMPAR-regulatory protein (TARP) auxiliary subunits, resulting in an accumulation of AMPARs in the PSD that underlies synaptic potentiation. 6) The stability of the modified PSD is maintained by the stability of the CaMKII-GluN2B complex. 7) By a process of subunit exchange or interholoenzyme phosphorylation CaMKII maintains synaptic potentiation in the face of CaMKII protein turnover. There are many other important proteins that participate in enlargement of the synaptic spine or modulation of the steps that drive and maintain the potentiation. In this review we critically discuss the data underlying each of the steps. As will become clear, some of these steps are more firmly grounded than others, and we provide suggestions as to how the evidence supporting these steps can be strengthened or, based on the new data, be replaced. Although the journey has been a long one, the prospect of having a detailed cellular and molecular understanding of learning and memory is at hand.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that CaMKII is both necessary and sufficient for NMDAR-dependent LTP induction and also maintains synaptic strength/memory, with CaMKII-GluN2B binding and T286 autophosphorylation as central mechanisms. It synthesizes biochemical, electrophysiological, imaging, and genetic evidence and highlights unresolved questions about downstream targets and maintenance.

Key findings

  • CaMKII inhibition blocks LTP induction; constitutively active CaMKII enhances AMPAR EPSCs roughly two- to threefold, selectively over NMDAR EPSCs, and occludes LTP.
  • Blocking CaMKII after LTP with myr-CN27 reduces control AMPAR EPSCs by ~50% and fully reverses established LTP; CRISPR deletion of CaMKII reduces synaptic transmission to ~50% of control.
  • CaMKII binding to GluN2B is required: CaMKII I205K prevents binding and blocks LTP; CA CaMKII with I205K fails to enhance; replacing GluN2B with L1298A/R1300Q reduces AMPAR responses ~50%.
  • T286 autophosphorylation is central: T286A replacement blocks LTP, and autophosphorylation increases Ca2+/CaM affinity >1,000-fold (15 nM to 20 pM); CaMKII has low Ca2+ sensitivity (apparent Kd = 1.6 µM; Hill coefficient ~6) versus resting Ca2+ (20–50 nM).

Methods

  • Narrative review of published literature on NMDAR-dependent LTP and CaMKII; no new experimental data or systematic search/meta-analysis are reported.
  • Focuses primarily on CA3-to-CA1 hippocampal synapses and the first hour of LTP, integrating biochemical, electrophysiological, imaging, genetic, and computational studies.
  • Figures are modified from prior studies; the review discusses three models of LTP expression (receptor-centric, PSD-centric, vesicle-centric).

Limitations

  • Stated: the review is limited to NMDAR-dependent LTP, primarily the first hour, and does not cover all LTP forms.
  • Stated: critical downstream targets of CaMKII remain elusive; LLPS role is speculative; T286 phosphorylation requirement for maintenance is debated; role of CaMKIIβ and S1303 phosphorylation unresolved.
  • Evident: as a narrative review, it does not systematically assess study quality, publication bias, or effect sizes across the literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1152/physrev.00034.2022

Cites

447 of 447 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

374 of 692 cited sources checked · 205 supported · 10 flagged · accuracy not yet measured

  • Premisecitation

    Voltage pulse potentiation (VPP) typically is transient, lasting no longer than 20 min.

    “the potentiation typically is transient, lasting no longer than 20 min (Refs. 189–193, but see Refs. 194, 195).”
    Quote in the paperSubstantial claim3 of 7 sources checked
    • cites [189] source
    • cites [190] source
    • cites [191] source
    • cites [192] source
    • cites [193] source

      The Results (Fig. 4A,B; page not given in our copy) report that potentiation induced by depolarizing pulses often decayed back to control, supporting its transient nature. The reported decay time is 10–30 minutes, so the source does not support the claim that it lasts no longer than 20 minutes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [194] source

      In 'Induction of non-Hebbian LTP by postsynaptic depolarization' (page unavailable), the paper contrasts an earlier transient result with its own stable potentiation, observed for nearly an hour without a tendency to decay. The cited paper therefore provides an exception to the stated 20-minute limit, consistent with the citing sentence’s 'but see' qualification, rather than evidence for that limit. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [195] source

      The Methods section describes how voltage-pulse LTP was induced, and “Postsynaptic Syt1,7 loss blocks LTP” discusses its mechanism. Neither passage states that the potentiation is typically transient or lasts no longer than 20 minutes; searches for voltage-pulse LTP duration and decay found no such statement in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Premisecitation

    Filipodia account for roughly 30% of synapses in the mature brain.

    “The anatomical substrate for silent synapses is fingerlike dendritic protrusions referred to as filipodia (245), which account for roughly 30% of synapses in the mature brain (240).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [245] source

      The Results (page unavailable) report that filopodial synapses were 21% of identified contacts in developing CA1 during the first postnatal week and fell to 7.2% by postnatal day 12—not roughly 30% in the mature brain. The paper also states that dendritic filopodia disappear as the cortex matures; it does not report a 30% estimate for mature-brain synapses. (LLM, conf=0.82)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [240] source
  • Interpretationreasoning

    The existence of LTD avoids the problem of saturation, which could be essential for a mnemonic device.

    “The existence of LTD avoids the problem of saturation, which could be essential for a mnemonic device (366–371).”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [366] source
    • cites [367] source
    • cites [368] source

      In “The Stability Problem” (page unavailable), the paper groups LTP and LTD as learning-related plasticity mechanisms, then says such mechanisms can create destabilizing feedback that drives neuronal activity to saturation. It says nervous systems need other plasticity mechanisms to counteract those forces; it does not say that the existence of LTD avoids saturation. (LLM, conf=0.86)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [369] source

      The paper’s discussion of memory lifetimes says that balancing synaptic potentiation and depression can improve memory performance. But its discussion of saturation describes effects distinct from the mechanism it proposes; our copy does not establish that LTD itself avoids saturation or that this is essential for a mnemonic device. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [370] source

      The Results section on single-synapse models describes LTD and says that both LTP and LTD should saturate, but does not say that the existence of LTD prevents synaptic saturation. The Discussion’s “Functional significance” section links maintained dynamic range to learning and memory, attributing it to the interaction of Hebbian and homeostatic plasticity rather than to LTD alone. I searched for the proposed LTD–saturation–memory link; no passage in our copy establishes it. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [371] source

      Section 4.4.3 discusses saturation of LTP/LTD after repeated spike pairings, and Section 4.4.1 discusses the need for synaptic stability to retain memories. Neither passage says that LTD prevents saturation in a memory device. Searches for LTD preventing saturation and for depression preventing synaptic-weight saturation found no passage making that connection. (LLM, conf=0.70)

      Experimental — accuracy not yet measured
  • Premisecitation

    Plateau potentials on their own do not change synaptic strength.

    “These plateau potentials on their own do not change synaptic strength.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [424] source

      The Results section, “Plateau increase the amplitude of incoming input” (page unavailable), says plateau-induced place fields are consistent with increased EPSP amplitude—evidence of strengthened synaptic input. The Discussion (page unavailable) also describes plasticity produced by plateau potentials. The paper therefore makes the contrary point, although it does not isolate a plateau from all concurrent synaptic input. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [426] source

      The Role of BTSP section (page not provided) says Ca2+ plateau potentials drive BTSP and can induce plasticity in a single trial, contrary to the claim that they do not change synaptic strength. The paper does not separately test a plateau in the absence of synaptic input, so its statement does not establish that plateaus are sufficient without input. (LLM, conf=0.79)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Synaptic capture of AMPARs requires the PDZ domain interaction between TARPs and PSD-95.

    “It is also agreed that the synaptic capture of AMPARs requires the PDZ domain interaction between TARPs and PSD-95 (275, 279, 294, 440).”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [275] source

      The Introduction describes TARP–PSD-95 PDZ binding as a major mechanism of AMPAR localization, but the Discussion explicitly rejects it as a universal requirement. It reports that the GluA2 N-terminal domain can support synaptic anchoring even without γ8 PDZ ligands. (LLM, conf=0.89)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [279] source
    • cites [294] source

      The Discussion reports that a functional TARP PBM–PSD-95 PDZ interaction is necessary for TARP-assisted AMPAR accumulation at synapses. Its Limitations section narrows that conclusion to the TARP γ-8-based trafficking studied and notes that some synaptic transmission may be TARP independent. The unqualified claim that synaptic capture of AMPARs requires this interaction therefore goes beyond the paper's findings. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [440] source

      The section on TARP/MAGUK interactions says TARP–PSD-95 interactions stabilize AMPARs at the postsynaptic density and involve PSD-95 PDZ domains. It calls these interactions the most plausible AMPAR capture sites, but does not establish that this specific interaction is universally required; the reported requirement for the TARP binding motif comes from particular experimental conditions. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 145
  • Classified as probably not a substantial claim. 42
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationcitation

    The expression of NMDAR-dependent LTP is primarily postsynaptic, although a minor presynaptic component is difficult to entirely exclude.

    “Although it is difficult to entirely exclude the possibility of a minor presynaptic component of NMDAR-dependent LTP, the evidence is overwhelming that its expression is primarily postsynaptic.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [17] source
    • cites [18] source
    • cites [19] source
    • cites [22] source

      In the Introduction’s “The AMPAR code and LTP” section (page unavailable), the paper describes NMDAR-dependent LTP as resulting from increased postsynaptic AMPAR density and/or conductance, supporting primarily postsynaptic expression. Our copy does not address whether a minor presynaptic component is difficult to exclude; a search for “presynaptic” found no discussion of that qualification. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [31] source

      The Introduction says presynaptic mechanisms can play an important, even dominant, role in some experimental situations. The Discussion concludes that early LTP can be entirely presynaptic, entirely postsynaptic, or a combination of both. The paper therefore does not treat presynaptic expression as merely a minor possibility or postsynaptic expression as generally predominant. (LLM, conf=0.93)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    The prevailing model posits that LTP-mediated covalent modification of the intracellular CTD of GluA1 results in capture of modified GluA1-containing receptors by preexisting slots in the PSD.

    “The prevailing model posits that LTP-mediated covalent modification of the intracellular CTD of GluA1 results in the capture of these modified GluA1-containing receptors by preexisting “slots” in the postsynaptic density (PSD) (17, 18, 212).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [17] source

      In “Proposed Working Models for LTP” (page unavailable), the paper describes capture by preexisting PSD slots as one of three possible models, not the prevailing model. It explicitly says that C-terminal domains would be modulatory but not essential to that capture; modification of other receptor domains or auxiliary subunits would play the essential role. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [18] source
    • cites [212] source

  • May combine two claims.

    Premisecitation

    CaMKII phosphorylates Kalirin at T75, and this phosphorylation is sufficient to enhance synaptic transmission.

    “CaMKII phosphorylates Kalirin at T75 (Ref. 315, but see Ref. 317), and this phosphorylation is sufficient to enhance synaptic transmission.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [315] source
    • cites [317] source

      In Results and Discussion (‘Kalirin phosphorylation is brain region specific’; page unavailable), the paper says its in vitro studies found CaMKII phosphorylation at T79, not the T75 site named in the claim. The cited passage also does not show that phosphorylation at T75 is sufficient to enhance synaptic transmission. (LLM, conf=0.83)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Both sLTP and LTP are greatly diminished in a CaMKII-dead mutant (K42K or K42M), despite its translocation.

    “In support of these results, both sLTP (379) and LTP (121, 379) are greatly diminished in a CaMKII-dead mutant (K42K or K42M), despite its translocation.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [379] source

      The sections on tetanus-induced spine structural plasticity and LTP report severely impaired spine enlargement and LTP, while the postsynaptic-dynamics section reports preserved translocation. The mutant studied is K42R, however, not the K42K or K42M mutant named in the claim. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [121] source

      The Discussion (page unavailable) says that substantial LTP remained with the CaMKIIα K42R mutation, contrary to the claim that LTP was greatly diminished in the kinase-dead mutant. The Results report loss of long-term sLTP with a different mutant, T286A; they do not establish the claimed sLTP result for K42K or K42M, or its translocation. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    At CA1 excitatory synapses, both NMDAR-dependent and NMDAR-independent forms of LTP can coexist under certain conditions.

    “There is even evidence that at CA1 excitatory synapses both NMDAR-dependent and NMDAR-independent forms of LTP can coexist under certain conditions (49–51).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [49] source
    • cites [50] source
    • cites [51] source

  • Classified as probably not a substantial claim.

    Premisecitation

    Long-term potentiation (LTP) is brief repetitive synaptic stimulation that results in long-lasting increases in synaptic strength.

    “long-term potentiation (LTP), in which brief repetitive synaptic stimulation results in long-lasting increases in synaptic strength, was gaining popularity as a cellular model for learning and memory (16–22).”
    Quote in the paperSubstantial claim3 of 7 sources checked
    • cites [16] source
    • cites [17] source
    • cites [18] source
    • cites [19] source
    • cites [20] source
    • cites [21] source
    • cites [22] source

      The Introduction describes LTP as a change in synaptic strength associated with learning and memory, and the ‘AMPAR code and LTP’ section describes enhanced synaptic AMPARs during LTP. The passages do not establish the claim’s specific induction condition: brief repetitive synaptic stimulation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Weak repetitive synaptic stimulation can elicit an NMDA-dependent decaying potentiation referred to as short-term potentiation (STP).

    “For instance, weak repetitive synaptic stimulation can elicit an NMDA-dependent decaying potentiation referred to as short-term potentiation (STP) (99–101).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [99] source
    • cites [100] source
    • cites [101] source

  • May combine two claims.

    Premisecitation

    Once Ca2+/CaM dissociates from a T286-phosphorylated kinase, autonomous activity phosphorylates T305 and T306, blocking Ca2+/CaM rebinding and braking further stimulation.

    “However, once Ca2+/CaM dissociates from a kinase phosphorylated at T286, its autonomous activity quickly phosphorylates T305 and T306, blocking rebinding of Ca2+/CaM and exerting a brake on further Ca2+/CaM stimulation, in what is at times referred to as inhibitory autophosphorylation (80, 84–86).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [80] source

      The Results report that phosphorylation at T286 produces autonomous activity and that removal of Ca2+ triggers a rapid inhibitory burst of autonomous autophosphorylation. Figure 8 depicts phosphorylation of a serine and a threonine after Ca2+/calmodulin dissociates, reducing further Ca2+/calmodulin-dependent activity. Our copy does not identify those inhibitory residues as T305 and T306 or establish that inhibition occurs by blocking Ca2+/calmodulin rebinding. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [84] source
    • cites [85] source
    • cites [86] source

  • May combine two claims.

    Premisecitation

    T286 autophosphorylation is primarily intersubunit within a holoenzyme, although at very high kinase concentration it can also occur by an interholoenzyme mechanism.

    “This autophosphorylation is primarily intersubunit autophosphorylation within a holoenzyme, although at very high kinase concentration it can also occur by an interholoenzyme mechanism (FIGURE 2B4) (71, 79–81).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [71] source
    • cites [79] source
    • cites [80] source

      The discussion (page unavailable in our copy) identifies threonine 286 as the autophosphorylation site responsible for autonomous kinase activity. It does not establish that phosphorylation is primarily between subunits of one holoenzyme or that phosphorylation between holoenzymes occurs at very high kinase concentrations; searches for those mechanisms found no supporting passage. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [81]

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

  • May combine two claims.

    Premisecitation

    Ca2+/CaM binding peels off the regulatory segment from the kinase surface, unlocking catalytic competency and providing access to substrates and interacting proteins.

    “The binding of Ca2+/CaM peels off the regulatory segment from the surface of the kinase, thus unlocking constraints on catalytic competency and providing access to substrates and CaMKII interacting and anchoring proteins (e.g., GluN2B, Tiam1, and CaMKIIN) (61).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    BTSP is NMDAR dependent and, unlike classical LTP, has a coincidence time window of seconds rather than milliseconds.

    “It is NMDAR dependent, but unlike classical LTP the coincidence time window is seconds, not milliseconds.”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [103] source

      The Introduction describes BTSP as acting within a seconds-long window, and the Results section on initial membrane voltage says BTSP induction requires NMDA-type glutamate receptors, citing prior work and reporting an experiment consistent with that requirement. The Discussion contrasts BTSP with the short-timescale synchrony of traditional Hebbian plasticity, but our copy does not specify a millisecond coincidence window for classical LTP. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [104] source
    • cites [105] source

      The Introduction (page unavailable) says BTSP affects inputs active several seconds before a burst and calls it a departure from conventional plasticity schemes, supporting the seconds-scale distinction. The available passages do not state that BTSP is NMDAR dependent or explicitly quantify classical LTP’s window in milliseconds. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [106] source

  • May combine two claims.

    Premisecitation

    The I205K mutant that blocks docking of GluN2B to the kinase also blocks clustering, suggesting that the regulatory segment and GluN2B have an overlapping docking site.

    “Self-association occurring in transfected cells was used to show that the I205K mutant that blocks docking of GluN2B to the kinase also blocks clustering, suggesting that the regulatory segment and GluN2B have an overlapping docking site (134).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Two aspects of kinase structure reduce clustering, the CaMKIIβ subunit and T286 phosphorylation, but these are countered by the high CaMKII concentration at the PSD.

    “Two aspects of kinase structure reduce clustering, one is the CaMKIIβ subunit and another is T286 phosphorylation, but these are countered by the high CaMKII concentration at the PSD (134, 135).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [134] source

      The section “Role of Thr286 autophosphorylation in CaMKII self-association” (page unavailable) reports that a phosphorylation-mimicking Thr286 mutation strongly reduced self-association, supporting the T286 part of the claim. The passages examined do not show that the CaMKIIβ subunit reduces clustering or that a high CaMKII concentration at the PSD counteracts either effect; the Discussion describes a concentrating effect of self-association, not that counteraction. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [135] source

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

    Premisecitation

    In the forebrain the ratio is roughly 3 α to 1 β, and holoenzymes are composed of both subunits.

    “In the forebrain the ratio is roughly 3 α to 1 β, and holoenyzmes are composed of both subunits (155–157).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [155] source
    • cites [156] source

      The subunit-composition results report a 3:1 α:β ratio in material precipitated with the α-specific antibody and show that forebrain holoenzymes containing both subunits exist. The Discussion also says the preparation contains α-only homomers, so the claim is too broad if it means all holoenzymes contain both subunits; the paper reports a 2:1 ratio for the heteromers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [157] source

  • May combine two claims.

    Premisecitation

    Inactive CaMKIIα, but not β, binds to Shank3, and when it is activated it dissociates.

    “Inactive CaMKIIα, but not β, binds to Shank3, and when it is activated it dissociates (161).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    CaMKIINtides inhibit kinase activity with high affinity by binding across the entire substrate binding site and therefore also block GluN2B binding.

    “They inhibit kinase activity with high affinity by binding across the entire substrate binding site (FIGURE 2B7) (61, 147, 153), and therefore also block GluN2B binding (152, 154).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [61] source
    • cites [147] source

      The Results and discussion report that AIP potently inhibits CaMKII and binds a substrate-binding site. The paper studies AIP, not CaMKIINtides, and does not establish binding across the entire substrate-binding site. The citing sentence attaches different references to the GluN2B claim, so that part is not attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [153] source

  • May combine two claims.

    Premisecitation

    The linker length affects CaM affinity and Ca2+ spike frequency sensitivity as well as rates of autophosphorylation.

    “The linker length affects CaM affinity and Ca2+ spike frequency sensitivity (69, 158) as well as rates of autophosphorylation (159).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [69] source
    • cites [158] source
    • cites [159] source

  • May combine two claims.

    Premisecitation

    Upon activation CaMKIIβ dissociates from F-actin because of competition with Ca2+/CaM for the F-actin binding region, and dissociation is made more persistent by specific autophosphorylation of CaMKIIβ in the F-actin binding region.

    “Upon activation CaMKIIβ dissociates from F-actin because of competition with Ca2+/CaM for the F-actin binding region, and dissociation is made more persistent by specific autophosphorylation of CaMKIIβ in the F-actin binding region (171–174).”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [171] source
    • cites [172] source

      The Results sections on phosphorylation of the F-actin-binding region report that Ca2+/CaM reduces CaMKIIβ binding to F-actin and that autophosphorylation in that region prevents binding from recovering after Ca2+ chelation (page not provided). But the paper describes competition as a possible steric-hindrance mechanism involving adjacent binding domains, not an established competition for the same F-actin-binding region. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [173] source
    • cites [174] source

      The Results section, “Activation of CaMKII Leads to a Loss of Bundling Activity” (page not provided), reports that Ca2+/calmodulin activation reverses CaMKIIβ-mediated F-actin bundling and that autophosphorylation contributes to a longer-lasting reversal. It does not establish that Ca2+/calmodulin competes specifically for the F-actin-binding region, or identify specific phosphorylation sites there as the cause of persistent dissociation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Interpretationcitation

    The CaMKIIα-Shank3 complex may serve as a nearby tethered reservoir pool of CaMKII.

    “It is proposed that this CaMKIIα-Shank3 complex may serve as a nearby tethered reservoir pool of CaMKII (161).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Brief large-amplitude signals favor potentiation, whereas more modest long-duration signals favor depression.

    “Brief large-amplitude signals favor potentiation, whereas more modest long-duration signals favor depression (181).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Deletion of CaMKIIβ impairs LTP, as does deletion of CaMKIIα.

    “Interestingly, deletion of CaMKIIβ impairs LTP (121, 172, 175), as does the deletion of CaMKIIα.”
    Quote in the paperNot a substantial claim3 of 3 sources checked

  • May combine two claims.

    Premisecitation

    Activating VDCCs, which are present in spines, evokes cytosolic spine Ca2+ transients and the activation of cytosolic spine CaMKII.

    “Activating VDCCs, which are present in spines, evokes cytosolic spine Ca2+ transients (185–187) and the activation of cytosolic spine CaMKII (188).”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [185] source
    • cites [186] source
    • cites [187] source
    • cites [188] source

  • May combine two claims.

    Premisecitation

    Expression of active CaMKII or direct delivery into the cell via the recording electrode has repeatedly revealed a roughly two- to threefold enhancement in the AMPAR EPSC but little change in the NMDAR EPSC.

    “Expression of active CaMKII (121, 130–132, 209, 210, 212) or direct delivery into the cell via the recording electrode (199) has repeatedly revealed a roughly two- to threefold enhancement in the AMPAR EPSC but little change in the NMDAR EPSC (130–132).”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [121] source

      In Results, ‘CaMKII constitutive activity and the maintenance of LTP’ (Fig. 10; page unavailable), expression of constitutively active CaMKIIα increased AMPAR EPSCs to about 250% of control. The cited passages do not report NMDAR EPSCs for that active-kinase experiment, so they do not establish the claimed little change in NMDAR EPSCs. Direct delivery through a recording electrode is attributed to a different citation in the citing sentence. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [130] source
    • cites [131] source

      The Results (Fig. 2; page not specified in our copy) report that expression of active αCaMKII increased AMPAR EPSCs to 3.73 ± 0.9 times control, with no significant change in NMDAR EPSCs. This supports the selective enhancement, but the reported mean is above the claimed roughly two- to threefold range. The recording-electrode delivery method is cited separately in the citing sentence, not attributed to this paper. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [132] source
    • cites [209] source

  • May combine two claims.

    Premisecitation

    Using a T286D mutation alone is problematic because it generates a constitutively active kinase that then results in phosphorylation of T305/T306, which can counteract T286D and alter resident time at the synapse.

    “Just using a T286D mutation would be problematic because it generates a constitutively active kinase that then results in the phosphorylation of T305/T306, which can counteract T286D and alter resident time at the synapse (88, 210, 211).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [88] source
    • cites [210] source

      The Results describe T286D as an active form of CaMKII and hypothesize that it might autophosphorylate T305/T306; they do not establish that this phosphorylation necessarily occurs. The Results and Discussion show that T305/T306 phosphorylation can counteract T286D-associated potentiation, and the Discussion says it reduces binding to the postsynaptic density. The paper does not report a change in residence time at the synapse (page numbers unavailable in our copy). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [211] source

      The Results and Discussion (pages unavailable) describe T286D as constitutively autonomous and report that T305/306 phosphorylation is expected to follow its activity and can inhibit further Ca²⁺/calmodulin stimulation and reduce GluN2B binding. They also report a possible further reduction in synaptic localization, significant by t test but not ANOVA. The paper does not measure synaptic residence time, so that specific effect is not established. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Most AMPARs in CA1 hippocampal pyramidal cells are tetraheteromeric assemblies of either GluA1/GluA2 or GluA2/GluA3 subunits, with a preponderance of GluA1/GluA2.

    “Most AMPARs in CA1 hippocampal pyramidal cells are tetraheteromeric assemblies of either GluA1/GluA2 subunits or GluA2/GluA3 subunits with a preponderance of GluA1/GluA2 subunits (264–266).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [264] source
    • cites [265] source
    • cites [266] source

      The immunoprecipitation results report that most complexes in the CA1/CA2 pyramidal-neuron preparation contain GluR1/GluR2 or GluR2/GluR3. Our copy does not establish a four-subunit assembly for those complexes or a clear preponderance of GluR1/GluR2 over GluR2/GluR3, and the preparation includes CA2 as well as CA1 (pages unavailable in the indexed copy). (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activity-dependent synaptic recruitment of AMPARs may involve two steps: delivery to the PSD, then addition to AMPAR clusters in the nanocolumn.

    “It is suggested that activity-dependent synaptic recruitment of AMPARs may involve two steps (259, 261). First, AMPARs are delivered to the PSD, but this is not enough to increase synaptic strength. Second, the newly recruited AMPARs are added to AMPAR clusters in the nanocolumn.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [259] source
    • cites [261] source

  • May combine two claims.

    Premisecitation

    Replacement with GluN2B(L1298A-R1300Q) reduces AMPAR responses by approximately 50%, similar to the reduction seen by deleting CaMKII.

    “Intriguingly, AMPAR responses were reduced ∼50%, similar to the reduction seen by deleting CaMKII”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [121] source

      The Results (Fig. 9 caption; page not provided) report that replacement with GluN2Bmut left AMPAR responses at 48.5% of control. The Results and Discussion also report an approximately 50% reduction after CaMKIIα deletion. Our copy does not identify GluN2Bmut as L1298A-R1300Q, so that specific mutation designation remains unverified. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Replacement of wild-type GluN2B with GluN2B(L1298A-R1300Q) has no effect on NMDAR synaptic currents, indicating that the mutant is functional.

    “Replacement with the mutant GluN2B had no effect on NMDAR synaptic currents, indicating that it is functional.”
    Quote in the paperSubstantial claim2 of 2 sources checked

  • May combine two claims.

    Premisecitation

    AMPARs are highly mobile in the extrasynaptic membrane and can diffuse into and out of the synapse.

    “Furthermore, AMPARs are highly mobile in the extrasynaptic membrane and can diffuse into and out of the synapse (20).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    CaMKII phosphorylates SynGAP and decreases its binding to PSD-95.

    “CaMKII phosphorylates SynGAP and decreases its binding to PSD-95 (302, 304).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [302] source
    • cites [304] source

  • May combine two claims.

    Premisecitation

    Phosphomimic mutations of TARP serines greatly diminish both binding of the TARP CTD to PSD-95 and rescue of AMPAR transmission in AMPAR-deleted cells.

    “Phosphomimic mutations greatly diminished both the binding of the TARP CTD to PSD-95 and the rescue of AMPAR transmission in AMPAR-deleted cells.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [288] source

      The Results and Significance passages report that deleting TARP γ-8’s PDZ-binding motif prevented rescue of synaptic currents in AMPAR-deleted cells; a separate passage says phosphor-null mutations did not fully rescue basal transmission. Neither passage reports the claimed effect of phosphomimic serine mutations, and the PSD-95 binding experiment described in our copy concerns GluK1/Neto1 rather than the TARP CTD. No page numbers are provided in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [289] source

  • May combine two claims.

    Premisecitation

    CaMKII phosphorylation of TARP serines neutralizes charge, releasing the CTD and providing access to the PDZ domains of PSD-95.

    “CaMKII phosphorylation of the serines neutralizes the charge, releasing the CTD and providing access to the PDZ domains of PSD-95 (284, 285, 287).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [284] source

      The Results section identifies TARPγ-8 serines phosphorylated by CaMKIIα. The Discussion describes phosphorylation-related electrostatic changes releasing the cytoplasmic domain from membrane lipids and enabling PSD-95 interaction, but specifically for TARPγ-2. It does not establish that CaMKII phosphorylation of TARPγ-8 neutralizes charge and exposes its PSD-95-binding site. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [285] source

      The Discussion (‘Roles of multiple phosphorylation sites in TARPs’; page unavailable) says acidic phosphorylated serines inhibit the electrostatic interaction of stargazin’s basic residues with negatively charged lipid bilayers. The Results (‘Lipid bilayers inhibit binding of stargazin to PSD-95’; page unavailable) say phosphorylation permits dissociation from lipids and binding to PSD-95. Our copy does not identify CaMKII as the kinase responsible for this mechanism, so that attribution is unsupported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [287] source

  • May combine two claims.

    Premisecitation

    Binding of AMPAR/TARPs to PSD-95 is important for synaptic targeting and LTP.

    “Since the binding of AMPAR/TARPs to the PSD protein PSD-95 is known to be important for synaptic targeting and LTP (278, 279)”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [278] source
    • cites [279] source

      In “The role of TARPs in AMPAR surface trafficking and synaptic targeting” (page not provided), the review says stargazin binds PSD-95 and that this interaction is important for AMPAR synaptic targeting. The same section reports that a phospho-null stargazin construct prevents LTP, but it does not establish that binding to PSD-95 itself is important for LTP. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Overexpression of PSD-95 potentiates AMPAR EPSCs and occludes LTP, and the S73D mutant causes similar potentiation.

    “since overexpression of PSD-95 on its own potentiates AMPAR EPSCs and occludes LTP (131, 297, 298) and the S73D mutant causes a similar potentiation.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [131] source

      The Results (Figure 2) attribute increased AMPAR EPSCs to expression of activated αCaMKII, not PSD-95. Searches for PSD-95 overexpression, LTP occlusion, and the S73D mutant found no passage addressing those claims in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [297] source
    • cites [298] source

      The section on PSD-95-induced synaptic potentiation reports that PSD-95 expression potentiates AMPAR responses and prevents further LTP; the Discussion describes this as occlusion. The mutant-results section discusses C3,5S, AAAA, Double, and PDZ1-2 constructs, but the passages returned for searches on S73D and Ser73 do not support the claim that S73D causes similar potentiation. Page numbers were not available in our copy. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Interfering with actin polymerization blocks both sLTP and LTP.

    “Interfering with actin polymerization blocks both sLTP (247) as well as LTP (310).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [247] source
    • cites [310] source

      Citation 310 supports the LTP portion of the sentence, not the separately cited sLTP portion. In “LTP induction is inhibited by actin polymerization inhibitors” (page unavailable), the paper reports that latrunculin B reduced potentiation rather than completely blocking LTP, so “blocks” overstates its finding. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Knockdown of SynGAP results in accumulation of synaptic AMPARs, which occludes chemLTP.

    “Furthermore, knockdown of SynGAP results in the accumulation of synaptic AMPARs, which occludes chemLTP (304).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    On average there are approximately 250 PSD-95 molecules in the PSD and approximately 50 AMPARs, although this number is highly variable.

    “On average there are ∼250 PSD-95 molecules in the PSD (65) and, on average, ∼50 AMPARs, although this number is highly variable (143, 290, 291).”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [65] source
    • cites [143] source

      The Analysis of AMPAR- and NMDAR-Type Structures by EM Tomography section reports variability in AMPAR counts, including a relationship with PSD size, but estimates 105 ± 52 AMPARs in an average-sized PSD—not approximately 50. The ∼250 PSD-95 figure has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [290] source

      The paper reports substantial variability in AMPA-receptor content across rat hippocampal synapses (Figure 8), supporting the variability qualifier. It does not establish approximately 50 AMPARs as an overall average: its estimates differ by synapse type, and it calculates an average of 81 functional receptors for juvenile mossy-fiber synapses. The PSD-95 figure is attached to a different citation and is not assessed here. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [291] source

  • May combine two claims.

    Premisecitation

    Alanine substitutions of critical serines in the TARP CTD reduce AMPAR EPSCs but do not affect the magnitude of LTP.

    “Furthermore, alanine substitutions of the critical serines in the TARP CTD, although reducing AMPAR EPSCs, do not affect the magnitude of LTP (288).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [288] source

      The passage supplied under Significance (page not given) reports that phosphor-null mutations in tethered TARP γ-8 did not fully rescue basal synaptic transmission, while LTP was normal. This supports the direction of both effects, but the paper's finding is limited to tethered γ-8 with homomeric GluA1 receptors; the passage does not identify the substitutions as alanine, and it cautions that phosphorylation might matter for heteromeric AMPARs. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Tiam1 has a CaMKII binding domain homologous to the GluN2B CTD, and Tiam1-CaMKII complex formation results in constitutive CaMKII activity.

    “The authors find that Tiam1 has a CaMKII binding domain. This domain is homologous to the GluN2B CTD, and thus the Tiam1-CaMKII complex formation results in constitutive CaMKII activity.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [314] source

      The Results sections on Tiam1 binding and reciprocal activation (page unavailable) identify a CaMKII-binding region in Tiam1 and report that the formed complex maintains CaMKII activity without Ca2+/calmodulin. They describe that region as homologous to CaMKII’s autoinhibitory domain, not to the GluN2B C-terminal domain. The claimed GluN2B homology is therefore unsupported by our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Expression levels of Tiam1 in the CA1 region of the hippocampus are very low, and deleting Tiam1 has no effect on synaptic transmission.

    “A caveat to this proposal is that the expression levels of Tiam1 in the CA1 region of the hippocampus are very low and deleting Tiam1 has no effect on synaptic transmission (320).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [320] source

      The CA1 neurotransmission section reports low Tiam1 expression and no detectable change in AMPAR- or NMDAR-mediated currents after Tiam1 shRNA knockdown. The Discussion likewise limits the finding to baseline glutamatergic transmission at Schaffer collateral–CA1 synapses. The claim says Tiam1 was deleted and extends the result to synaptic transmission generally; the cited experiment tested knockdown, not deletion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    RhoGEFs kalirin-7, Trio, and Tiam are expressed in spines and phosphorylated by CaMKII.

    “The RhoGEFs that have received the most attention are kalirin-7, Trio, and Tiam, which are all expressed in spines and phosphorylated by CaMKII (314–317).”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [314] source

      The Introduction describes Tiam1 and Kalirin-7/Trio as CaMKII substrates involved in spine formation and development. The Results place Tiam1 in a stimulated spine, but the cited passages do not establish that all three are expressed in spines; the paper also does not say they have received the most attention. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [315] source
    • cites [316] source

      In “Discovery and expression” (page unavailable), the review places Kal7 in dendritic spines; “Protein structure and signaling” says CaMKII is among the kinases that target Kalirin. The Tiam1 “Electrophysiology and synaptic function” section places Tiam1 in spines and reports calcium-dependent phosphorylation, but does not identify CaMKII as the kinase. The cited passages do not establish that Trio is expressed in spines or phosphorylated by CaMKII, so the claim that all three share both properties is not supported. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [317] source

      The Results and Discussion section (page unavailable) states that Kal7 is concentrated at the postsynaptic density and that in vitro studies show CaMKII phosphorylates Kal7 at T79. The paper does not establish that Trio or Tiam are expressed in spines or phosphorylated by CaMKII, so it supports the claim only for kalirin-7. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The Tiam1 mechanism may be involved in the dentate gyrus, where Tiam1 expression is high and does contribute to synaptic transmission.

    “However, such a mechanism may well be involved in the dentate gyrus, where Tiam1 expression is high and does contribute to synaptic transmission (320).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Maintenance of segregation in the LLPS study required T286 autophosphorylation but did not require phosphorylation of any other component of the reconstituted system.

    “Importantly, although the maintenance of this segregation in the LLPS study required T286 autophosphorylation, it did not require the phosphorylation of any other component of the reconstituted system.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    When the CTD of neuroligin 1 is included, it partitions with AMPAR/TARPs but not with NMDARs, reminiscent of nanocolumns in the PSD.

    “Remarkably, when the CTD of neuroligin 1 is included, it partitions with the AMPAR/TARPs but not with the NMDARs, reminiscent of nanocolumns in the PSD (251–253)”
    Quote in the paperSubstantial claim4 of 4 sources checked
    • cites [323] source
    • cites [251] source
    • cites [252] source

      In “Lateral patterning of cytosolic PSD components” (page unavailable), the paper reports that AMPARs and NMDARs occupy separate synaptic zones in EM tomography and that TARPs associate with AMPAR scaffolds. But it does not report that the CTD of neuroligin-1 partitions with AMPAR/TARPs rather than NMDARs; its “Candidate mechanisms of trans-synaptic alignment” section instead describes neuroligin-1 as broadly distributed over the PSD. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [253] source

      The Discussion (page not specified) reports that AMPAR and NMDAR clusters barely colocalize at the nanoscale, supporting the comparison to distinct PSD domains. It does not report that the CTD of neuroligin 1 partitions with AMPAR/TARPs rather than NMDARs. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Recovery from bleaching spine SEP-GluA1 following glutamate uncaging shows a modest dependence on CaMKII, while single SEP-GluA1 exocytotic events during glutamate uncaging appear to be independent of CaMKII.

    “Sixth, whereas the recovery from bleaching spine SEP-GluA1 following glutamate uncaging shows a modest dependence on CaMKII, single SEP-GluA1 exocytotic events during glutamate uncaging appear to be independent of CaMKII (250).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    AMPAR-containing vesicles are associated with synaptotagmin-1, which is involved in LTP.

    “Additional support for the vesicle-centric model is the finding that AMPAR-containing vesicles (obtained by immunoisolation) are associated with such proteins as synaptotagmin-1 (341), which is involved in LTP (195).”
    Quote in the paperSubstantial claim2 of 2 sources checked

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

    Premisecitation

    Stx-4 is reported to be required for LTP.

    “while on the other hand Stx-4 is reported to be required for LTP (336, 338).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [336] source
    • cites [338] source

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

    Premisecitation

    Stx-3 is reported to be required for LTP.

    “On the one hand Stx-3 is reported to be required for LTP (Ref. 334, but see Ref. 339)”
    Quote in the paperNot a substantial claim2 of 2 sources checked

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationcitation

    If the contribution of CaMKII to synaptic transmission were a net gain that simply adds onto the preexisting excitatory drive of the cell, the system would be unstable and quickly saturate.

    “If this were the case, it has been argued that the system would be unstable and quickly saturate (366–371).”
    Quote in the paperNot a substantial claim5 of 6 sources checked
    • cites [366] source
    • cites [367] source

      In §II, the paper says that if synapses are allowed only to increase, all will eventually saturate. It also says that its activity-dependent modification threshold is necessary for a bounded state. This supports the general concern about unchecked synaptic gain, but the paper does not address CaMKII or establish that saturation would occur quickly. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [368] source

      In “The Stability Problem” (page not provided), the paper argues that unconstrained strengthening of excitatory synapses creates positive feedback that can drive neuronal activity to saturation. It does not make that argument specifically about a net additive contribution from CaMKII; its discussion of CaMKII in “Signaling Pathways Underlying Synaptic Scaling” concerns different homeostatic effects. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [369] source

      In the section on power-law forgetting (page unavailable), the paper says that imbalances between synaptic strengthening and weakening spoil its memory-performance result, and that a repeatedly potentiated synapse can reach a point where it becomes no stronger. It does not connect this to CaMKII adding to a cell’s preexisting excitatory drive, or say that such a gain would make the system unstable and quickly saturate. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [370] source

      The Introduction says that Hebbian plasticity is a positive-feedback process whose synaptic weights are typically unstable until they reach saturation. The Results discuss CaMKII as a possible mechanism of Hebbian LTP, but do not establish that CaMKII adds a net gain to preexisting excitatory drive or that this specific arrangement would quickly saturate. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [371] source

      Section 4.1, Pair-based STDP rules (page unavailable), says that an additive plasticity model has an unstable fixed point and that individual synaptic weights move to their upper or lower bounds. It does not make this argument about CaMKII or say saturation is quick. It also says the neuron's mean firing rate is stabilized, so instability of individual weights should not be described as instability of the whole system. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Homeostasis occurs on a slower timescale of many hours or days; the cell senses excess activity and through a cellwide mechanism scales down all synapses in a multiplicative manner to restore excitatory drive to a set point.

    “The third mechanism, homeostasis, occurs on a slower timescale of many hours or days (368). In this case the cell senses the excess level of activity and through a cellwide mechanism scales down all synapses in a multiplicative manner to restore excitatory drive to a set point.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    Ca2+/CaM peeling away the autoinhibitory segment results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state.

    “The first step involves Ca2+/CaM peeling away the autoinhibitory segment from the kinase domain. This results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state (64, 78, 119–121, 221).”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [64] source
    • cites [78] source
    • cites [119] source

      The Introduction (page not provided) says Ca2+/CaM exposes CaMKII’s catalytic site and that binding to NR2B then keeps CaMKII active independently of its phosphorylation state. It mentions Thr286 autophosphorylation as a requirement for a proposed second NR2B binding site, but does not say that Ca2+/CaM exposure results in Thr286 phosphorylation or that this phosphorylation maintains activity. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [120] source
    • cites [121] source

      The Introduction (page not available) says Ca2+/CaM relieves CaMKII autoinhibition and that T286 autophosphorylation produces kinase activity that persists after Ca2+/CaM is removed. The Discussion identifies GluN2B as a CaMKII binding partner, but the paper does not establish that binding occurs without prior autophosphorylation or that the binding itself maintains CaMKII in an active state. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    NMDAR-dependent long-term depression (LTD) depresses synaptic transmission and can reverse established LTP.

    “Second, NMDAR-dependent long-term depression (LTD) depresses synaptic transmission and can reverse established LTP (374, 375) (see sect. 9.2.3).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [374] source
    • cites [375] source

      In the section headed “NMDA Receptor-Dependent LTD” (page unavailable), the review describes LTD of basal synaptic responses and says that blocking NMDARs blocks LTD. It also says synaptic activity can reverse LTP, but calls that phenomenon “depotentiation”; it does not establish that NMDAR-dependent LTD is what reverses established LTP. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    As long as Ca2+/CaM is present, binding and phase separation are maintained even with a phosphonull mutant of T286 (T286A) or with a kinase-dead mutant of CaMKII, although the binding of CaMKII to GluN2B is modestly enhanced by T286 phosphorylation.

    “As long as Ca2+/CaM is present, binding and phase separation are maintained even with a phosphonull mutant of T286 (T286A) (78, 169, 323, 377) or with a kinase-dead mutant of CaMKII (169, 323, 378, 379), although the binding of CaMKII to GluN2B is modestly enhanced by T286 phosphorylation (378).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [78] source
    • cites [169] source
    • cites [323] source

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

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Spine CaMKII activity as monitored with FRET imaging during LTP only remained elevated for ∼1 min after the induction of LTP, suggesting that conformational changes associated with CaMKII activation due to either Ca2+/CaM or autophosphorylation are transient.

    “Second, spine CaMKII activity as monitored with fluorescence resonance energy transfer (FRET) imaging (188) during LTP only remained elevated for ∼1 min after the induction of LTP, suggesting that conformational changes associated with CaMKII activation due to either Ca2+/CaM or autophosphorylation are transient.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [188] source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Phosphatase PP2A rapidly dephosphorylates CaMKII, which results in the dissolution of the CaMKII-GluN2B complex.

    “Further support for the role of T286 phosphorylation in maintaining the condensates and the binding of CaMKII to GluN2B in the absence of Ca2+/CaM is the finding that phosphatase PP2A rapidly dephosphorylates CaMKII, which results in the dissolution of the CaMKII-GluN2B complex (161).”
    Quote in the paperSubstantial claim1 of 1 sources checked

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

    Interpretationreasoning

    The higher concentrations of inhibitor that do reverse LTP could result from the displacement of GluN2B bound to CaMKII.

    “The higher concentrations of inhibitor that do reverse LTP (154, 361) could result from the displacement of GluN2B bound to CaMKII.”
    Quote in the paperNot a substantial claim2 of 2 sources checked

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

    Findingcitation

    T305/T306 phosphorylation selectively promotes LTD.

    “Finally, another proposal also focuses on CaMKII and the phosphorylation of T305/T306, which selectively promotes LTD (402).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    LTP is associated with a long-lasting increase in spine size, including a late increase in the size of the PSD and a slow increase in the size of the presynaptic bouton.

    “LTP is associated with a long-lasting increase in spine size (247, 248), including a late increase in the size of the PSD (56, 213, 414, 415) and additionally a slow increase in the size of the presynaptic bouton (213, 414).”
    Quote in the paperSubstantial claim4 of 6 sources checked
    • cites [247] source
    • cites [248] source
    • cites [56] source

      The Results section reports delayed PSD enlargement after structural LTP, and the Discussion describes PSD remodeling beginning about 60 minutes after induction. Our copy also reports persistent spine enlargement, but the passages located for presynaptic bouton growth do not report a slow increase in bouton size. That part of the claim is unsupported by this source. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [213] source
    • cites [414] source

      The Introduction says spine enlargement after LTP can persist for hours to days, and the Results report PSD enlargement at 2 hours. The Results also show enlargement of presynaptic active zones, but do not establish a slow increase in the size of the presynaptic bouton itself. Page numbers are not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [415] source

      The Introduction and PSD-reorganization section describe spine enlargement after LTP and PSD growth that lags spine-volume growth by hours. The Discussion mentions presynaptic bouton volume change, but does not establish the claimed slow increase in bouton size. The paper also reports that late-phase spine volume was not significantly different from controls. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    BTSP has been reproduced in slices, with the plateau potential induced by strong postsynaptic depolarization.

    “BTSP has been reproduced in slices (104) (FIGURE 12, A–C). In this case the plateau potential is induced by strong postsynaptic depolarization.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    More recent studies have found evidence that high kinase concentration enables subunit exchange and transphosphorylation between subunits within a holoenzyme can occur in the absence of Ca2+/CaM but on a much slower time course.

    “However, more recent studies have found evidence that high kinase concentration enables subunit exchange and transphosphorylation between subunits within a holoenzyme can occur in the absence of Ca2+/CaM but on a much slower time course (406).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    CaMKIIα, but not CaMKIIβ, can self-associate at least at reduced pH or high concentration, and this requires displacement of the autoinhibitory domain.

    “It is interesting to note that CaMKIIα, but not CaMKIIβ, can self-associate, at least at reduced pH or high concentration and this requires displacement of the autoinhibitory domain (133–135).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [133] source
    • cites [134] source

      The section on pH-dependent clustering reports that αCaMKII forms clusters at reduced pH in the presence of elevated Ca²⁺, and the Discussion proposes release of the autoregulatory domain as a step in self-association. Our copy does not establish that CaMKIIβ cannot self-associate or that high concentration alone permits CaMKIIα self-association; it presents the domain-displacement mechanism as a model rather than a demonstrated requirement. Page numbers are unavailable in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [135] source

  • May combine two claims.

    Findingcitation

    Autophosphorylation occurs by transphosphorylation between subunits within a holoenzyme, but the substrate subunit needs to be bound to Ca2+/CaM because that is what exposes T286.

    “Although autophosphorylation does occur by transphosphorylation between subunits within a holoenzyme, the substrate subunit needs to be bound to Ca2+/CaM because that is what exposes T286 (82, 83), thus challenging the model of perpetuating CaMKII activity.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [82] source
    • cites [83] source

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

    Premisecitation

    Protein synthesis is proposed to be required for "late" LTP.

    “Protein synthesis is also proposed to be required for “late” LTP (55–57) (see sect. 3.3).”
    Quote in the paperNot a substantial claim3 of 3 sources checked

  • May combine two claims.

    Interpretationcitation

    Phosphorylation of inactive holoenzymes occurs when they are not bound to Ca2+/CaM, establishing a phosphorylation event for maintaining CaMKII activity in the face of protein turnover.

    “Although it can be argued as to whether this occurs through interholoenzyme phosphorylation or through subunit exchange, this finding shows that phosphorylation of inactive holoenzymes occurs (not bound Ca2+/CaM), thus establishing a phosphorylation event for maintaining CaMKII activity in the face of protein turnover.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingcitation

    The subunit exchange process requires CaMKII activation and is initiated after phosphorylation of T305/T306 in the CaM footprint, which blocks rebinding of CaM and frees the CaM-binding element to interact with the hub of the holoenzyme.

    “This subunit exchange process requires CaMKII activation and is initiated after phosphorylation of T305/T306 in the CaM footprint, which blocks rebinding of CaM and frees the CaM-binding element to interact with the hub of the holoenzyme (407).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [407] source

      The Introduction says phosphorylation of Thr 305/306 prevents Ca2+/CaM rebinding, and the Results and discussion describe activation-triggered exchange and a model in which the freed CaM-binding element interacts with the hub (pages not provided). But the paper says Thr 305/306 phosphorylation potentiates exchange; it does not establish that exchange must be initiated after that phosphorylation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    An inactive CaMKII holoenzyme can be phosphorylated on T286 in the absence of Ca2+/CaM.

    “Remaining to be demonstrated, if this mechanism is to propagate CaMKII activity, is that an inactive holoenzyme can be phosphorylated on T286 in the absence of Ca2+/CaM. This is what was demonstrated in the studies claiming to exhibit subunit exchange (406).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [406] source

      The Results and discussion section (Figure 5B; page unavailable) reports T286 phosphorylation in previously unactivated wild-type CaMKII mixed with active CaMKIIT286D. But the Figure 5 caption says the mixing experiments used wild-type CaMKII in the presence of Ca2+/CaM and ATP, so they do not demonstrate phosphorylation in its absence. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    These mutations increase autophosphorylation of T286 (or T287 in some isoforms) that further increases constitutive activity.

    “These in turn increase autophosphorylation of T286 (or T287 in some isoforms) that further increases constitutive activity (429, 430).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [429] source

      The “Mutations in CAMK2” section reports increased Thr286 autophosphorylation for two CAMK2A variants, and the Discussion says Thr286 autophosphorylation makes CAMK2A autonomously active (page numbers unavailable). But the paper describes heterogeneous effects: other variants reduce phosphorylation, and the constitutively active Thr286Pro variant cannot be phosphorylated at Thr286. The claim therefore overgeneralizes the mechanism to these mutations as a group. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [430] source

      The Results section reports increased Thr286/Thr287 phosphorylation in three mutants, although two increases were not statistically significant and no phosphorylation signal was observed for a fourth. The Discussion proposes that the variants may increase autophosphorylation and thereby increase Ca²⁺-independent activity; the citing sentence presents that proposed chain as established for the mutations. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Several dozen human mutations in CaMKII have been identified, and their molecular characteristics support many of the biochemical behaviors of CaMKII described above.

    “Several dozen human mutations in CaMKII have been identified, and their molecular characteristics support many of the biochemical behaviors of CaMKII described above.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [428] source

      The Introduction and Discussion describe biochemical effects of the human CAMK2A E183V mutation, including reduced kinase activity and altered protein interactions. The paper does not establish that several dozen human CaMKII mutations have been identified or characterize their molecular effects as a group; the Discussion instead focuses on one mutation. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [429] source

      The Distribution of the Variants section reports 19 distinct CAMK2A or CAMK2B variants in 24 people, not several dozen distinct mutations. The Mutations in CAMK2 section reports that variants alter autophosphorylation, supporting the point that their molecular characteristics bear on CaMKII biochemical behavior. The cited paper therefore supports the substance of the biochemical point but not the stated count. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [430] source

      The Discussion reports five de novo CAMK2A/CAMK2B variants identified in this study, not several dozen. The Results link some of those variants to reduced autoinhibition and increased Thr286/Thr287 autophosphorylation, supporting the claim that human variants illuminate CaMKII biochemistry, but not its stated number or breadth. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    E183V exhibits reduced interactions with GluN2B and other interacting proteins, consistent with a surface groove accommodating both substrates and anchoring proteins.

    “Consistent with a surface groove accommodating both substrates and anchoring proteins, it also exhibits reduced interactions with GluN2B and other interacting proteins.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Most of these molecules are in the pallium, just beneath the core of the PSD and not close enough to be bound to GluN2B.

    “Most of these molecules are in the pallium, just beneath the core of the PSD and not close enough to be bound to GluN2B (139).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [139] source

      The Results describe CaMKII labeling as concentrated particularly in the PSD pallium under stimulation. The Discussion says CaMKII molecules in the distal pallium are too far from NR2B (GluN2B) in the PSD core to bind it directly. It does not establish that most CaMKII molecules are too far away; it also reports labeling in the core. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The number of NMDARs at spine synapses and perhaps filopodia synapses is much less variable, averaging roughly 20, and this number is largely independent of PSD size.

    “The number of NMDARs at spine synapses and perhaps filopodia synapses is much less variable, averaging roughly 20, and this number is largely independent of PSD size (143, 438, 439).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [143] source

      The Analysis of AMPAR- and NMDAR-Type Structures by EM Tomography reports 23 ± 5 NMDAR-type structures in controls, nearly constant across PSD sizes; the Discussion estimates 20–30 per PSD. The study examined spine synapses, but our copy does not establish that the same pattern holds at filopodia synapses, even tentatively. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [438] source
    • cites [439] source

  • May combine two claims.

    Premisecitation

    Expression of the E183V mutant in neurons decreases spine density and synaptic transmission.

    “Expression of the mutant in neurons decreases spine density and synaptic transmission.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationcitation

    The R292P mutation is in the autoregulatory segment, and it is likely that disruption of its conformation by the presence of a proline reduces autoinhibition and produces increased autonomy that has a gain-of-function effect in the cytosol.

    “The mutation is in the autoregulatory segment, and it is likely that the disruption of its conformation by the presence of a proline reduces autoinhibition and produces increased autonomy that has a gain-of-function effect in the cytosol (432).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    The number of AMPARs at dendritic spine synapses is highly variable but averages roughly 50, and this number strongly correlates with the size of the PSD.

    “The number of AMPARs at dendritic spine synapses is highly variable but averages roughly 50 (143, 438, 439), and this number strongly correlates with the size of the PSD.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [143] source

      The Analysis of AMPAR- and NMDAR-Type Structures by EM Tomography reports a strong positive correlation between AMPAR-type structure count and PSD diameter (r = 0.87; Fig. 6A). It estimates 105 ± 52 AMPARs in an average-size PSD, not an average of roughly 50. Page numbers were not supplied for these passages. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [438] source
    • cites [439] source

  • May combine two claims.

    Interpretationcitation

    The finding that strong hyperpolarization before the plateau potential blunts the potentiation favors the CaMKII partial activation mechanism but does not rule out the metabotropic mechanism.

    “The finding that strong hyperpolarization before the plateau potential blunts the potentiation (103) favors the former but does not rule out the latter.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Although there is no change in the number of PSD-95 molecules, saturating LTP results in a two- to threefold enhancement of the AMPAR EPSC, as does the expression of constitutively active CaMKII.

    “Although there is no change in the number of PSD-95 molecules (56), saturating LTP results in a two- to threefold enhancement of the AMPAR EPSC, as does the expression of constitutively active CaMKII.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Blocking actin remodeling blocks both sLTP and LTP.

    “However, blocking actin remodeling blocks both sLTP (247) and LTP (310).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [247] source
    • cites [310] source

      Citation 310 is attached to the LTP portion of the sentence; the separate sLTP citation is not assessed here. In “LTP induction is inhibited by actin polymerization inhibitors” (page unavailable), latrunculin B reduced LTP, but potentiation remained at 113% versus 160% in controls. The source supports inhibition of LTP, not its complete blockade. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Actin is largely excluded from the core of the PSD, and evidence suggests that, at least for the first hour, the changes in spine size are not accompanied by changes in the size of the PSD.

    “Actin is largely excluded from the core of the PSD (66, 322), and evidence suggests that, at least for the first hour, the changes in spine size are not accompanied by changes in the size of the PSD (56).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [66] source
    • cites [322] source

      The Introduction describes the PSD as containing cytoskeletal components, but does not say whether actin is excluded from its core. The Results measure spine head width, not PSD size or changes during the first hour. Searches for both points found no passage in our copy that addresses them. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [56] source

  • May combine two claims.

    Premisecitation

    The number of NMDARs does not change during LTP, since constitutively active CaMKII does not affect the NMDAR EPSC and LTP is expressed primarily on the AMPAR.

    “The number of NMDARs does not change, since constitutively active CaMKII does not affect the NMDAR EPSC (130–132) and LTP is expressed primarily on the AMPAR (19).”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [130] source
    • cites [131] source

      The Results (Figure 2) report that constitutively active αCaMKII increased AMPAR EPSCs without a significant change in NMDAR EPSCs. The paper does not establish from that measurement that the number of NMDARs remains unchanged during LTP. The separate statement about LTP being expressed primarily on AMPARs is cited to another source in the printed sentence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [132] source
    • cites [19] source

  • May combine two claims.

    Interpretationcitation

    Recent work from Kuriyan and collaborators nicely fulfills the second requirement, although there may be an alternative mechanism of interholoenzyme phosphorylation.

    “The recent work from Kuriyan and collaborators (406) nicely fulfills this second requirement, although there may be an alternative mechanism of interholoenzyme phosphorylation (81).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [406] source
    • cites [81]

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

  • May combine two claims.

    Premisecitation

    Parallel to the electrophysiological changes during LTP is an enlargement of the spine and a widening of the spine neck.

    “Parallel to the electrophysiological changes during LTP is an enlargement of the spine and a widening of the spine neck (247, 248).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [247] source
    • cites [248] source

  • May combine two claims.

    Premisecitation

    LLPS orchestrates a phase-in-phase condensation of AMPAR/TARPs, PSD-95, and neuroligin1, largely independent of phosphorylation, although T286 phosphorylation is required for the maintenance of the condensates.

    “Most intriguingly, this orchestrates a phase-in-phase condensation of AMPAR/TARPs, PSD-95, and neuroligin1, largely independent of phosphorylation, although T286 phosphorylation is required for the maintenance of the condensates.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Findingreasoning

    myr-CN27 and myr-AIP lack a nonspecific presynaptic effect, since the depression of AMPAR EPSCs is not accompanied by any change in NMDAR EPSCs.

    “myr-CN27 and myr-AIP lack this nonspecific effect, since the depression of AMPAR EPSCs is not accompanied by any change in the NMDAR EPSC, thus ruling out any nonspecific presynaptic action.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Synaptic transmission in cells lacking CaMKII was approximately 50% of that of control cells, consistent with a maintenance role of CaMKII.

    “The synaptic transmission in cells lacking CaMKII was ∼50% of that of the control cells, consistent with a maintenance role of CaMKII.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In two-pathway experiments, after LTP stabilized, myr-CN27 fully reversed LTP and the responses converged with the control pathway, which was reduced by ∼50%.

    “After LTP stabilized, myr-CN27 was applied. LTP was fully reversed and the responses converged with the responses in the control pathway, which, as expected, were reduced by ∼50%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    LTP is often accompanied by a depression in neighboring nontetanized synapses, which would tend to renormalize excitatory drive onto the neuron.

    “First, it has been reported that LTP is often accompanied by a depression in neighboring nontetanized synapses (372, 373), which would tend to renormalize excitatory drive onto the neuron.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [372] source
    • cites [373] source

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

    Findingnone given

    Isolated CaMKII (unphosphorylated) in the absence of Ca2+/CaM has no intrinsic activity.

    “First, does isolated CaMKII (unphosphorylated) in the absence of Ca2+/CaM have any intrinsic activity? As discussed in sect. 2.1 this is most unlikely.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The subunit being phosphorylated apparently needs to have Ca2+/CaM bound; phosphorylation does not significantly occur on inactive subunits.

    “A further complication for either of these possibilities is that it appears that the subunit being phosphorylated apparently would need to have Ca2+/CaM bound, i.e., it does not significantly occur on inactive subunits (13, 15, 82, 83, 406).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] source
    • cites [15] source
    • cites [82] source

  • May combine two claims.

    Premisereasoning

    NMDARs are highly permeable to Ca2+, and the rise in intracellular Ca2+ provides the trigger for LTP.

    “As discussed in sect. 3, NMDARs are highly permeable to Ca2+ and it is the rise in intracellular Ca2+ that provides the trigger for LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The NMDAR ion channel is blocked by Mg2+ at normal cellular resting potentials, and depolarization relieves the block.

    “The reason for this is that the NMDAR ion channel is blocked by the binding of Mg2+ to the external side of the receptor at normal cellular resting potentials.”
    • Also stated in: § 2.1. LTP: Induction · plain
      “During the depolarization caused by a tetanus (or direct depolarization of the membrane by current injection through the recording electrode) the Mg2+ ion is electrostatically driven from its binding site, relieving the channel block.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    CaMKII is required for the induction of NMDAR-dependent LTP.

    “It is well accepted that CaMKII is required for the induction of NMDAR-dependent LTP”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    NMDAR-dependent and NMDAR-independent forms of LTP exist at different types of synapses.

    “It is well established that NMDAR-dependent and NMDAR-independent forms of LTP exist at different types of synapses [e.g., NMDAR-independent LTP at hippocampal mossy fiber synapses (48)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] source

  • May combine two claims.

    Premisenone given

    Displacing the autoinhibitory domain exposes and helps present T286 to a different active subunit that autophosphorylates it.

    “The action of displacing the autoinhibitory domain also exposes and helps to present T286 to a different active subunit that autophosphorylates it.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The autoinhibitory segment strongly inhibits the kinase by locking it in a conformation not optimal for phosphotransferase activity, reducing ATP affinity, occluding substrates, and constraining CaM binding.

    “The autoinhibitory segment serves to strongly inhibit the kinase by locking it in a conformation that is not optimal for its phosphotransferase activity, reducing affinity for ATP, occluding substrates from the active site, and constraining binding of CaM to an incomplete binding site in the regulatory segment (FIGURE 2B2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Activation of CaMKII is curtailed by insufficient cellular free CaM and by the relatively low affinity of unphosphorylated CaMKII for free Ca2+/CaM.

    “Activation is also curtailed by insufficient cellular free CaM for all its binding proteins, since a significant fraction of CaM is membrane bound and not available in the cytosol, and the relatively low affinity of unphosphorylated CaMKII for the free Ca2+/CaM (95).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] source

  • May combine two claims.

    Premisecitation

    T305A/T306A mutations increase CaMKII levels in PSDs and lower the threshold for LTP.

    “However, T305A/T306A mutations increase CaMKII levels in PSDs and lower the threshold for LTP (87).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] source

  • May combine two claims.

    Interpretationreasoning

    Autophosphorylation of T286 enables both fuller activation of CaMKII during a stimulus train and persistence of that activity after Ca2+ returns to baseline.

    “The comparisons with T286A make it clear that autophosphorylation of T286 enables both a fuller activation of CaMKII during a stimulus train and a persistence of that activity even after the Ca2+ level returns to baseline.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: During a brief Ca2+ spike there is only time for a fraction of a dodecamer to be occupied and activated by Ca2+/CaM.

  • May combine two claims.

    Interpretationreasoning

    The finding that CaMKII binding to GluN2B is essential for its synaptic action and that CaMKII-GluN2B has constitutive activity toward substrates suggests that either S1303 is not phosphorylated in the GluN2B-CaMKII complex or phospho-S1303 does not significantly prevent binding or inhibit activity.

    “the finding that the binding of CaMKII to GluN2B is essential for its synaptic action (see sect. 6) and constitutive activity of CaMKII-GluN2B toward substrates suggests that either S1303 is not phosphorylated in the GluN2B-CaMKII complex or phospho-S1303 does not significantly prevent binding or inhibit activity.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Autophosphorylation may cause CaMKII to suppress activation of other CaM-dependent enzymes by competing for Ca2+/CaM.

    “Given the high concentration of CaMKII at the synapse, one can anticipate that one effect of autophosphorylation, with the consequent increase in CaM affinity, is that CaMKII may suppress activation of other CaM-dependent enzyme by competing for Ca2+/CaM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The NMDAR has a central role in plasticity, both as a trigger via its Ca2+ permeability and as a scaffold required to sustain plasticity.

    “This further highlights the central role of the NMDAR in plasticity: not only as a trigger of the plasticity via its Ca2+ permeability but as a scaffold that is required to sustain the plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    CaMKII is not competitive for the limiting Ca2+/CaM in its basal state but markedly increases its affinity as it becomes autophosphorylated.

    “CaMKII is not competitive for the limiting Ca2+/CaM in its basal state but markedly increases its affinity as it becomes autophosphorylated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The CaMKII-GluN2B interaction is critical for maintaining the active state, for localizing CaMKII to the PSD, and therefore for LTP.

    “The interaction is therefore critical both for maintaining the active state as well as for localizing CaMKII to the PSD, and therefore for LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CaMKII self-association is not simply aggregation and may be important physiologically.

    “considerable evidence suggests that this phenomenon is not simply aggregation and may be important physiologically.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CaMKII has low intrinsic activity in the basal state and only achieves significant activity following induction of LTP and NMDA-mediated Ca2+ influx.

    “The major conclusion is that CaMKII has low intrinsic activity in the basal state and only achieves significant activity following induction of LTP and the NMDA-mediated Ca2+ influx.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    CaM is less abundant than the sum total of its interacting proteins, so there is competition for CaM.

    “CaM is less abundant than the sum total of its interacting proteins, so there is, in essence, a competition for CaM.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    For the CTD peptide to directly produce a constitutive kinase, one end of the GluN2B CTD may function as a wedge at the T site to block reassociation of the autoinhibitory segment while its other end is not tightly bound to the active S site so that substrates can bind.

    “For the CTD peptide to directly produce a constitutive kinase, one needs to propose that one end of the GluN2B CTD may function as a wedge at the T site to block reassociation of the autoinhibitory segment while its other end is not tightly bound to the active S site so that substrates can bind.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CaMKIIα but not CaMKIIβ supports a structural function of CaMKII in translocation of proteasomes to synaptic sites and clustering of CaMKII holoenzymes in response to low pH.

    “Finally, CaMKIIα but not CaMKIIβ supports a structural function of CaMKII in translocation of proteasomes to synaptic sites (160) and clustering of CaMKII holoenzymes in response to low pH (133).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [160] source
    • cites [133] source

  • May combine two claims.

    Premisecitation

    This clustering is reversible, but in the presence of phosphatase inhibitors it is longer lasting.

    “This clustering is reversible, but in the presence of phosphatase inhibitors it is longer lasting (141).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] source

  • May combine two claims.

    Premisecitation

    Self-association occurs with CaMKIIα but not with CaMKIIβ.

    “It occurs with CaMKIIα but not with CaMKIIβ (133).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] source

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

    Interpretationreasoning

    Much of the constitutive activity at the PSD following translocation might be due to the NMDAR and not T286P.

    “might suggest that much of the constitutive activity at the PSD following translocation is due to the NMDAR and not T286P.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clustering is inhibited by regulatory segment-derived peptides such as AC-3 and AIP that bind at the T site, but is not inhibited by even high levels of syntide-2, which only binds at the catalytic or S site.

    “clustering is inhibited by regulatory segment-derived peptides, e.g., AC-3 and AIP that bind at the T site, but is not inhibited by even high levels of syntide-2, which only binds at the catalytic or S site (133).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] source

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

    Premisenone given

    There are four CaMKII isoforms, but the α- and β-isoforms are the most abundant isoforms in brain.

    “There are four CaMKII isoforms, but the α- and β-isoforms are the most abundant isoforms in brain.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Translocation of CaMKII to the PSD might be accounted for by direct holoenzyme-NMDAR interactions.

    “might suggest that translocation is accounted for by such direct holoenzyme-NMDAR interactions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    There is a correlation between structural features necessary for phase separation and for LTP, consistent with a role of phase separation in LTP.

    “This also suggests a correlation between structural features necessary for phase separation and for LTP, consistent with a role of phase separation in LTP.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Several Ca2+-dependent protein kinases are expressed in hippocampal neurons, including PKA, PKC, and CaMKII.

    “Several Ca2+-dependent protein kinases are expressed in hippocampal neurons [e.g., PKA (via adenylyl cyclase subtypes 1 and 8), PKC, CaMKII].”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    The added requirement may be that holoenzymes bound to GluN2B also need to bind each other and form clusters, as this is a property of CaMKIIα but not of CaMKIIβ.

    “The added requirement may be that holoenzymes bound to GluN2B also need to bind each other and form clusters, as this is a property of CaMKIIα but not of CaMKIIβ (133).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] source

  • May combine two claims.

    Premisecitation

    The failure of CaMKIIβ to phase separate could be rescued by swapping its long hub linker with the shorter linker from CaMKIIα, and this chimera fully rescued LTP.

    “The failure of CaMKIIβ to phase separate could be rescued by swapping its long hub linker with the shorter linker from CaMKIIα, and this chimera fully rescued LTP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] source

  • May combine two claims.

    Premisecitation

    After the pairing protocol, robust LTP was recorded in pathway 1 (0 mV), but no LTP was recorded in pathway 2 (+70 mV).

    “robust LTP was recorded in pathway 1 (0 mV), but no LTP was recorded in pathway 2 (+70 mV).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] source

  • May combine two claims.

    Interpretationreasoning

    Pure α is fully functional because it is not sequestered by F-actin.

    “Pure α is fully functional because it is not sequestered by F-actin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Ca2+ entry through the NMDAR is not only necessary but instructive for LTP.

    “These experiments demonstrate that Ca2+ entry through the NMDAR is indeed not only necessary but instructive for LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    VPP does not occlude with LTP, strongly implying a mechanism distinct from LTP.

    “VPP does not occlude with LTP (189, 192), strongly implying a mechanism distinct from LTP.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [189] source
    • cites [192] source

  • May combine two claims.

    Premisecitation

    Loading postsynaptic cells with the Ca2+ chelator EGTA blocked LTP, suggesting that Ca2+ is necessary for LTP.

    “loading postsynaptic cells with the Ca2+ chelator EGTA blocked LTP (176), suggesting that Ca2+ is necessary for LTP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] source

  • May combine two claims.

    Premisecitation

    When the intracellular electrode contained a Ca2+ chelator, no LTP occurred in the individual cell, while normal LTP was recorded from the field electrode.

    “when the intracellular electrode contained a Ca2+ chelator no LTP occurred in the individual cell, while normal LTP was recorded from the field electrode”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] source

  • Classified as probably not a substantial claim.

    Premisenone given

    These recordings were made 48 h after transfection.

    “Third, these recordings were made 48 h after transfection.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The NMDA-induced translocation of CaMKII to the spine/PSD is dramatic and in large excess to the number of NMDARs in the PSD (∼20-30 NMDARs), so only a small fraction of the CaMKII holoenzymes recruited to the PSD can be directly bound to GluN2B.

    “The NMDA-induced translocation of CaMKII to the spine/PSD is dramatic, in large excess to the number of NMDARs in the PSD (∼20–30 NMDARs) (see sects. 3.3 and 13.2); thus only a small fraction of the CaMKII holoenzymes recruited to the PSD can be directly bound to GluN2B.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Even after tens of hours CaMKII has no effect on presynaptic transmitter release, since there is no change in the NMDAR response.

    “This finding indicates that even after tens of hours CaMKII has no effect on presynaptic transmitter release, since there is no change in the NMDAR response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The CaMKII I205K mutation prevents binding to GluN2B but is otherwise reported to function normally.

    “A third approach takes advantage of a point mutation of CaMKII (I205K), which prevents binding to GluN2B but otherwise reported to function normally (78)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] source

  • May combine two claims.

    Interpretationreasoning

    CaMKII fully accounts for the effects of the rise in Ca2+ and there is no need to postulate a CaMKII-independent parallel Ca2+ signaling pathway requirement for LTP.

    “they suggest that CaMKII fully accounts for the effects of the rise in Ca2+ and that there is no need to postulate a CaMKII-independent parallel Ca2+ signaling pathway requirement for LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    CaMKII both qualitatively and quantitatively precisely mimics LTP and LTP and CaMKII occlude one another.

    “The above findings indicate that CaMKII both qualitatively and quantitatively precisely mimics LTP and that LTP and CaMKII occlude one another.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The studies summarized in this section demonstrate the essential role of CaMKII in the induction of LTP but say nothing about the maintenance of LTP.

    “the studies summarized in this section demonstrate the essential role of CaMKII in the induction of LTP. They say nothing about the maintenance of LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the occlusion experiment, the naive control pathway showed a robust enhancement, whereas the response on the pathway expressing LTP was greatly diminished.

    “The naive control pathway showed a robust enhancement, whereas the response on the pathway expressing LTP was greatly diminished.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] source

  • Classified as probably not a substantial claim.

    Premisecitation

    Phosphorylation-induced dissociation of SynGAP from PSD-95 is proposed to free PDZ domains, creating slots for AMPARs/TARPs.

    “The phosphorylation-induced dissociation of SynGAP from the PSD-95 is proposed to free up PDZ domains, creating slots for AMPARs/TARPs (302).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [302] source

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The proposed competition between SynGAP and TARP binding to PDZ1/PDZ2 is unresolved.

    “However, a critical component of this model is the proposed competition between SynGAP and TARP binding to PDZ1/PDZ2 that is unresolved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Direct phosphorylation of GluA1 by CaMKII may play a modulatory role in LTP but is not essential.

    “These results suggest that, although the direct phosphorylation of GluA1 by CaMKII may play a modulatory role in LTP, it is not essential.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The evidence suggests that neither the CTD of AMPARs nor TARPs are likely to be the essential direct downstream target of CaMKII in LTP.

    “In summary, although still a matter of debate, the evidence suggests that neither the CTD of AMPARs nor TARPs are likely to be the essential direct downstream target of CaMKII in LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Autophosphorylation functions to make the docking site for GluN2B persistently available, and the CaMKII-GluN2B complex would serve as a hub for further protein complex assembly.

    “In this scenario the autophosphorylation functions to make the docking site for GluN2B persistently available and the CaMKII-GluN2B complex would serve as a hub for further protein complex assembly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the binding study, no autophosphorylation is necessary; the transient CaMKII-GluN2B complex transitions into a persistent form that remains constitutively active.

    “In the binding study, no autophosphorylation is necessary; the transient CaMKII-GluN2B complex transitions into a persistent form that remains constitutively active.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] source

  • May combine two claims.

    Interpretationcitation

    LLPS may be a general mechanism for assembly of PSDs, and changes in protein expression or phosphorylation can effect a desired change in synaptic strength via modulation of phase separation in the PSD.

    “As we explore mechanisms for recruiting AMPARs to the synapse it will be important to consider that LLPS may be a general mechanism for assembly of PSDs and that changes in protein expression or phosphorylation can effect a desired change in synaptic strength via modulation of phase separation in the PSD (301).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] source

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

    Premisenone given

    CaMKII is sufficient for LTP.

    “Since CaMKII is sufficient for LTP, it predicts that CaMKII activation initiates the exocytosis, but this has yet to be demonstrated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The evidence is compelling that CaMKII initiates a dramatic rearrangement of the cytoskeleton that is required for sLTP and most likely for LTP.

    “The evidence is compelling that CaMKII initiates a dramatic rearrangement of the cytoskeleton that is required for sLTP and most likely for LTP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Application of glutamate to somatic nucleated patches generates nanoamps of AMPAR-mediated current, consistent with a high density of surface AMPARs.

    “For instance, application of glutamate to somatic nucleated patches, which are devoid of excitatory synapses, generates nanoamps of AMPAR-mediated current (342), consistent with a high density of surface AMPARs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [342] source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisecitation

    CaMKII is both necessary and sufficient to initiate LTP.

    “As discussed above, early on it was shown that CaMKII is both necessary and sufficient to initiate LTP, thus solidifying their association.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In most studies in which blocking exocytosis blocks LTP, there is no decrease in basal synaptic transmission, suggesting at least two distinct exocytotic pathways, one for maintaining basal transmission and one dedicated to LTP.

    “Surprisingly, in most of the studies in which blocking exocytosis blocks LTP there is no decrease in basal synaptic transmission, suggesting that there are at least two distinct exocytotic pathways, one for maintaining basal transmission and one dedicated to LTP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Premisereasoning

    LTP requires an exocytotic event.

    “In the case of the vesicle-centric model of LTP, it seems clear the LTP requires an exocytotic event.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Field potential input-output curves used in many knockout mouse studies are not as sensitive as paired recordings from control and transfected cells.

    “It should be mentioned that field potential input-output curves used in many of the knockout mouse studies are not as sensitive as paired recordings from control and transfected cells used in the more recent investigations.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The reduction in synaptic transmission following inhibition of CaMKII reflects a reversal of prior LTP.

    “We imply in sect. 8 that the reduction in synaptic transmission following inhibition of CaMKII reflects a reversal of prior LTP.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The homeostatic mechanism is involved in maintaining the overall level of LTP on a pyramidal cell at roughly 50%.

    “Perhaps this homeostatic mechanism is involved in maintaining the overall level of LTP on a pyramidal cell at roughly 50%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Although the initial formation of CaMKII-GluN2B condensates by Ca2+/CaM can occur without phosphorylation, kinase activity and in particular T286 phosphorylation are required for the persistent maintenance of the condensates in the absence of Ca2+/CaM.

    “As discussed above, although the initial formation of CaMKII-GluN2B condensates by Ca2+/CaM can occur without phosphorylation, kinase activity, and in particular T286 phosphorylation, is required for the persistent maintenance of the condensates in the absence of Ca2+/CaM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    T286 phosphorylation in maintenance allows for bidirectional plasticity in the form of LTD, in which phosphorylated T286 is an obvious target of PP1.

    “It should be emphasized that T286 phosphorylation in maintenance allows for bidirectional plasticity in the form of LTD, in which phosphorylated T286 is an obvious target of PP1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The first requirement of the two-step model is a multimeric protein capable of intermolecular phosphorylation; CaMKII fully satisfies this requirement.

    “The first requirement is a multimeric protein capable of intermolecular phosphorylation. As reviewed, CaMKII fully satisfies this requirement.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Under baseline conditions the balance between phosphorylation and dephosphorylation favors phosphorylation.

    “These proposals suggest that under baseline conditions the balance between phosphorylation and dephosphorylation favors phosphorylation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Although autophosphorylation is not required for the formation of the CaMKII-GluN2B complex, it is critical for its stability and maintaining the potentiated state.

    “It is proposed that although autophosphorylation is not required for the formation of the CaMKII-GluN2B complex, it is critical for its stability and maintaining the potentiated state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    PP1 is the likely phosphatase for preventing spread of CaMKII active state, as it is concentrated in the PSD, whereas PP2A is abundant in cytoplasm, and CaMKII in PSD is preferentially dephosphorylated by PP1.

    “PP1 is the likely phosphatase for such a role, as it is concentrated in the PSD, whereas PP2A is abundant in the cytoplasm (64, 385, 386) and CaMKII in the PSD is preferentially dephosphorylated by PP1 (385).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [64] source
    • cites [385] source
    • cites [386] source

  • May combine two claims.

    Interpretationreasoning

    Individual CaMKII holoenzymes can move into and out of CaMKII-GluN2B condensates, but as long as a net threshold level of these complexes remains the condensate persists.

    “It is likely that individual CaMKII holoenzymes can move into and out of the condensates, but as long as a net threshold level of these complexes remains the condensate persists.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: For CaMKII to exert its effect it must be bound to GluN2B.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    In vivo ambient Ca2+/CaM levels, although not sufficient to significantly activate the enzyme, might allow transient binding of Ca2+/CaM that is permissive for intersubunit phosphorylation within a holoenzyme at T286.

    “It should also be considered that in vivo ambient Ca2+/CaM levels, although not sufficient to significantly activate the enzyme, might allow transient binding of Ca2+/CaM that is permissive for intersubunit phosphorylation within a holoenzyme at T286.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In such a scenario, there is no need for the condensate to be recycled; it is the contents of the condensate that would turn over.

    “In such a scenario, there is no need for the condensate to be recycled; it is the contents of the condensate that would turn over.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    The CaMKII cluster will be anchored in the PSD by more than one GluN2B, in which case the turnover of NMDARs can occur while preserving the anchoring of CaMKII to the PSD.

    “Furthermore, it seems reasonable that the CaMKII cluster will be anchored in the PSD by more than one GluN2B, in which case the turnover of NMDARs can occur while preserving the anchoring of CaMKII to the PSD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: For CaMKII to exert its effect it must be bound to GluN2B.

  • May combine two claims.

    Interpretationreasoning

    The peeling away of the regulatory domain caused by binding of Ca2+/CaM results in phosphorylation of T286 and translocation of CaMKII to the PSD, where it binds to the CTD of GluN2B.

    “The peeling away of the regulatory domain caused by the binding of Ca2+/CaM results in the phosphorylation of T286 (FIGURE 13, 2 to 3) and the translocation of CaMKII to the PSD, where it binds to the CTD of GluN2B (FIGURE 13, 3 to 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AMPARs are abundant on the extrasynaptic membrane and freely diffuse into and out of the PSD.

    “It is generally accepted that AMPARs are abundant on the extrasynaptic membrane and freely diffuse into and out of the PSD (329).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [329] source

  • May combine two claims.

    Interpretationreasoning

    Although T286 phosphorylation is not required for CaMKII's binding to GluN2B, it is likely that autophosphorylation would precede this binding and that the kinase would remain phosphorylated, barring a depotentiating stimulus.

    “Although T286 phosphorylation is not required for CaMKII’s binding to GluN2B, it is likely that autophosphorylation would precede this binding and that the kinase would remain phosphorylated, barring a depotentiating stimulus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The number of PSD-95 molecules is roughly 200-300, and the number of CaMKII holoenzymes is estimated to be roughly 80.

    “The number of PSD-95 molecules is roughly 200–300 (65), and the number of CaMKII holoenzymes is estimated to be roughly 80 (65).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] source

  • May combine two claims.

    Interpretationreasoning

    BTSP is a homosynaptic form of LTP that requires NMDAR activation.

    “In summary, BTSP is a homosynaptic form of LTP that requires NMDAR activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Pharmacological blockade of NMDARs blocks BTSP, suggesting that the eligibility trace requires NMDAR activation.

    “Pharmacological blockade of NMDARs blocks BTSP (FIGURE 12E), suggesting that the eligibility trace requires NMDAR activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Although it is well established that CaMKII phosphorylates numerous synaptic proteins, an essential role for CaMKII phosphorylation of many of these targets largely remains elusive.

    “It should be pointed out that, although it is well established that CaMKII phosphorylates numerous synaptic proteins (66, 434–437), as reviewed here, despite intensive research an essential role for CaMKII phosphorylation of many of these targets largely remains elusive.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [66] source
    • cites [434] source
    • cites [435] source
    • cites [436] source
    • cites [437] source

  • May combine two claims.

    Interpretationreasoning

    Such a depolarization is expected to unblock some NMDAR and result in a small influx of Ca2+, which by itself would not be sufficient to alter synaptic strength.

    “Such a depolarization is expected to unblock some NMDAR and result in a small influx of Ca2+, which by itself would not be sufficient to alter synaptic strength.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    The plateau potential would provide a sufficient rise in Ca2+ to fully activate CaMKII.

    “The plateau potential would provide a sufficient rise in Ca2+ to fully activate CaMKII.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Such a complex provides a substrate for propagating autophosphorylated CaMKII, which turns over in ~2 wk, either through subunit exchange of inactive subunits into active holoenzymes or by interholoenzyme phosphorylation.

    “It provides a substrate for propagating autophosphorylated CaMKII, which turns over in ∼2 wk, either through subunit exchange of inactive subunits into active holoenyzmes or by interholoenyzme phosphorylation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The complex is positioned close to the postsynaptic membrane and PSD via the tether to NMDARs and provides an excess of spare docking sites for NMDARs on the CaMKII holoenzyme network.

    “It is positioned close to the postsynaptic membrane and PSD via the tether to NMDARs and provides an excess of spare docking sites for NMDARs on the CaMKII holoenzyme network.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CaMKII fulfills the first requirement beautifully, and recent evidence suggests that this autonomy is responsible for maintaining LTP.

    “As summarized in this review, CaMKII fulfills this requirement beautifully, and recent evidence suggests that this autonomy is responsible for maintaining LTP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Bound CaMKII far outnumbers the NMDARs, indicating that the large clusters are anchored to the PSD by the minority of subunits that directly bind to the NMDARs.

    “Thus, bound CaMKII far outnumbers the NMDARs, indicating that the large clusters are anchored to the PSD by the minority of subunits that directly bind to the NMDARs (FIGURE 14).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationcitation

    Although there is considerable evidence linking LTP to behavior memory, more evidence is needed to solidify this link.

    “However, although there is considerable evidence linking LTP to behavior memory (45, 441–443), more evidence is needed to solidify this link.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [45] source
    • cites [441] source
    • cites [442] source
    • cites [443] source

  • May combine two claims.

    Interpretationreasoning

    There are far more PSD-95 molecules in the PSD compared to AMPARs, suggesting that a substantial number of PSD-95 molecules are not available for capturing AMPARs.

    “Yet there are far more PSD-95 molecules in the PSD compared to AMPARs. These findings suggest that a substantial number of PSD-95 molecules are not available for capturing AMPARs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Activated CaMKII binds to the COOH terminus of GluN2B and is postulated to undergo self-association and promote LLPS.

    “Activated CaMKII binds to the COOH terminus of GluN2B and is postulated to undergo self-association and promote LLPS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These morphological changes involve actin-based cytoskeletal remodeling and will impact both biochemical and electrical compartmentalization.

    “These morphological changes involve actin-based cytoskeletal remodeling (see sect. 7.4.3) and will impact both biochemical and electrical compartmentalization.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Such a complex could shield the active CaMKII from phosphatases.

    “It could shield the active CaMKII from phosphatases.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These findings might suggest a dissociation of structural and physiological LTP.

    “These findings might suggest a dissociation of structural and physiological LTP.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Presumably in this LLPS reorganization, PSD-95 molecules previously not available for AMPAR/TARPs become unmasked.

    “Presumably in this LLPS reorganization, PSD-95 molecules previously not available for AMPAR/TARPs become unmasked.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The events that occur during LTP can be roughly divided into three components: formation of the CaMKII-GluN2B complex, recruitment of AMPARs, and structural changes.

    “The events that occur during LTP can be roughly divided into three components: 1) the formation of the CaMKII-GluN2B complex, 2) the recruitment of AMPARs, and 3) structural changes.”
    Quote in the paperSubstantial claim
178 of 178

  • The authors state this as an assumption.

    During a brief Ca2+ spike there is only time for a fraction of a dodecamer to be occupied and activated by Ca2+/CaM.

    “A reasonable assumption is that during a brief Ca2+ spike there is only time for a fraction of a dodecamer to be occupied and activated by Ca2+/CaM.”

  • The authors state this as an assumption.

    With the near-saturating pairing protocol used to induce LTP, the majority of the subunits of a holoenzyme would be phosphorylated.

    “It is assumed that with the near-saturating pairing protocol used to induce LTP the majority of the subunits of a holoenzyme would be phosphorylated (see last Ca2+ pulse in FIGURE 3B2).”

  • The authors state this as an assumption.

    With the standard saturating induction protocol used for LTP, the kinase would be highly phosphorylated, perhaps only limited by the availability of CaM.

    “It is assumed that with the standard saturating induction protocol used for LTP the kinase would be highly phosphorylated, perhaps only limited by the availability of CaM.”

  • The authors state this as an assumption.

    Native CaMKII holoenzymes are composed of a mixture of α- and β-isoforms.

    “Assuming that native CaMKII holoenzymes are composed of a mixture of α- and β-isoforms”

  • The paper relies on this without support.

    Memories can last for the entire span of an animal’s life.

    “Although memories can last for the entire span of an animal’s life, most synaptic proteins generally have half-lives of 2–5 days (403, 404).”

  • The authors state this as an assumption.

    The assembly of CaMKII holoenzymes involves transient free dimer subunits.

    “Assuming that the assembly of CaMKII holoenzymes involves transient free dimer subunits, perhaps these inactive dimers could be a source for subunit exchange.”

  • The paper relies on this without support.

    For CaMKII to exert its effect it must be bound to GluN2B.

    “We know that for CaMKII to exert its effect it must be bound to GluN2B.”
7 of 7

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?

  • CaMKII binding to GluN2B initiates structural rearrangements within the PSD and promotes the accumulation of AMPARs, contributing to synaptic potentiation.

    “This interaction initiates structural rearrangements within the PSD and promotes the accumulation of AMPARs, contributing to synaptic potentiation [53].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [53]

    Section 13.2 (page unavailable) links the CaMKII–GluN2B complex to proposed PSD reorganization and AMPAR recruitment during LTP. But it explicitly calls the proposed phase-separation mechanism speculative, so the citing sentence presents a possible mechanism as established. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The CaMKII-GluN2B complex may act as a 'tag' that captures N-cadherin dimers to increase synapse size and release sites, providing informational stability analogous to DNA base-pairing.

    “This complex may act as a ‘tag’ that captures N-cadherin dimers to increase synapse size and release sites, providing informational stability analogous to DNA base-pairing [53,63].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [53]

    Section 6 describes CaMKII–GluN2B complexes anchored at the postsynaptic density, and section 13.2 proposes that a network of these complexes helps retain synaptic information. Neither passage says the complex captures N-cadherin dimers, increases release sites, or provides stability analogous to DNA base-pairing; searches for those terms found no supporting passage. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Upon NMDAR activation and calcium influx, CaMKII becomes activated and translocates to the PSD, where it binds to GluN2B.

    “Upon NMDAR activation and calcium influx, CaMKII becomes activated and translocates to the PSD, where it binds to GluN2B.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [53]

  • Calcium influx into the dendritic spine is the critical trigger for LTP.

    “This calcium influx is the critical trigger for LTP.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [53]

  • NMDARs function as coincidence detectors, requiring both presynaptic glutamate release and sufficient postsynaptic depolarization to relieve their magnesium block and allow calcium influx into the dendritic spine.

    “NMDARs function as “coincidence detectors,” requiring both presynaptic glutamate release and sufficient postsynaptic depolarization to relieve their magnesium block and allow for calcium influx into the dendritic spine.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [53]

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.

  • CBP concentration is given as both 1.1 mM and 190 μM

    Minor

    The Figure 5 caption assigns two different concentrations to the CBP-containing microelectrodes in the same experimental group.

  • References 200 and 217 identify the same journal pages as different articles

    Minor

    The two entries have the same authors, journal, volume, pages, year, and PubMed identifier, but give different titles and DOIs.

2 of 2

Cites

Flagged first, then by citations

3 of the 450 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Lomo T, 1966, Acta Physiol Scand, 68
  2. Hebb DO. Organization of Behavior . New York: Wiley, 1949.
  3. Mangels LA, 1990, Mol Pharmacol, 37, 820

Cited by

Sorted by citations

Related

Authors
Nicoll, R. A., & Schulman, H.
Affiliations
  • University of California, San Francisco (US)
  • Stanford Medicine (US)
Corresponding author
  • Nicoll, Roger A.
  • Schulman, Howard
ORCID
Venue
Physiological Reviews
Publisher
American Physiological Society
Published
2023-10-01
Volume
103
Issue
4
Pages
2897-2945
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
DOI
10.1152/physrev.00034.2022
PMC
PMC10642921
OpenAlex
W4379791499
Semantic Scholar
30be6d9c7745f99a172f05da7cde7684da8c8aed
Cited by
126
References
450
Citations by year
2026: 34 · 2025: 55 · 2024: 33 · 2023: 4
FWCI
4.98
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Physiological Reviews (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
HHS | NIH | National Institute of Mental Health (NIH (R01MH117139))
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
CaMKII, synaptic memory, long-term potentiation, NMDA receptor, GluN2B, autophosphorylation, postsynaptic density, liquid-liquid phase separation, PSD-95, synaptic potentiation, synaptic spines, memory reconsolidation
MeSH terms
Animals, Hippocampus, Learning, Memory, Long-Term Potentiation, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

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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