The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index; 6 of the 54 sources its claims cite were checked for support.
Synaptic evidence for the efficacy of spaced learning
Open accessAbstract
The superiority of spaced vs. massed training is a fundamental feature of learning. Here, we describe unanticipated timing rules for the production of long-term potentiation (LTP) in adult rat hippocampal slices that can account for one temporal segment of the spaced trials phenomenon. Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used. Analyses of F-actin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were “missed” by the first stimulation bout. Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions, suggesting that intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections. We propose that a combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictate that the repetitions be widely spaced. Thus, the synaptic mechanisms described here provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.
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Written from the paper’s full text.
TL;DR
In adult rat hippocampal slices, a second theta burst stimulation delivered 60 min or more after the first produced additional LTP, whereas shorter delays did not, and this added potentiation recruited synapses missed by the first train. The findings suggest intrinsic spine threshold differences plus delayed membrane insertion events impose a spacing requirement that may explain one temporal component of distributed practice.
Key findings
- TBS2 at 10 or 30 min after TBS1 caused short-term but not additional long-term facilitation; at 60 min it doubled potentiation, and 90 min gave the same degree of LTP as 60 min. A third train at 60 min again increased potentiation, whereas a fourth and fifth had no effect.
- F-actin labeling showed TBS2 doubled the population of densely F-actin-positive spines above TBS1 alone; in GFP–phalloidin experiments, TBS1 left about 10% of spines with high F-actin versus 18% after TBS2 (P < 0.04), and the percentage of 5-μm dendritic segments with two or more labeled spines doubled after TBS2 (P < 0.005).
- Single-spine glutamate uncaging enlarged only ∼40% of targeted adult spines, compared with >80% of young spines (P < 0.005); adult spines that enlarged were refractory to successive induction even when uncaging events were separated by more than 1 h.
- Brefeldin A applied after TBS1 blocked additional LTP by TBS2 and caused LTP1 to decay; the ampakine CX614 increased LTP1 and substantially reduced LTP2.
Methods
- Acute hippocampal slices from young adult male Sprague–Dawley rats or C57BL/6 mice; Schaffer–commissural afferents in field CA1b were stimulated with TBS consisting of 10 bursts of 4 pulses at 100 Hz separated by 200 ms, with baseline/test responses at 3 pulses/min. Brefeldin A and CX614 were bath-applied at 20 μM.
- F-actin was imaged with Alexa Fluor 568–phalloidin and GFP-expressing mice using confocal microscopy; single-spine glutamate uncaging used two-photon imaging/uncaging in eGFP mice (2–3 or 8–10 wk), MNI-caged L-glutamate, and a >50% spine volume change threshold.
- Electrophysiology data are group means ± SEM with two-tailed Student t tests unless otherwise noted, significance at P < 0.05; spine volume statistics used t tests, one-way ANOVA, and repeated-measures ANOVA in SPSS and Excel.
Limitations
- Stated: the paper calls for future research on whether transcriptional mechanisms interact with the synapse-specific processes described, on longer intervals (days, weeks), and on unknown cell biological variables; the mechanism of the late priming step remains unresolved.
- Stated: brefeldin after TBS1 unexpectedly caused LTP1 to decay, and predicted AMPA receptor insertion would increase EPSPs at 30–60 min after TBS1, which was not observed, requiring alternative explanations.
- Evident: the findings are from acute hippocampal slices rather than behavioral learning or memory tests, and the uncaging experiments do not state the sex of the mice used.
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Claims the paper makes
31 Own result · 27 Own interpretation · 24 Not checked yet · 4 No basis given · 2 Own method · 1 Partly supported · accuracy not yet measured
None of the sources cited for this claim have been checked yet.
In the paper
“TBS, in addition to its actions on kinases, causes the breakdown of actin crosslinking proteins in the subsynaptic cytoskeleton; the relevant proteases also cleave transmembrane adhesion receptors that play a critical role in LTP-related actin polymerization (40–42).”
What the sources say
- Could not verifycites [40] Vanderklish PW, et al. Marking synaptic activity in dendritic spines with a calpain substrate exhibiting fluorescence resonance energy transfer. Proc Natl Acad Sci USA. 2000;97:2253–2258. doi: 10.1073/pnas.040565597. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceExperimental — accuracy not yet measured
The Results describe calpain cleavage of a reporter containing a spectrin cleavage site, and the Discussion links calpain activity generally to cytoskeletal remodeling. Our copy does not say that calpain cleaves transmembrane adhesion receptors or that such receptors are critical to LTP-related actin polymerization (searched: adhesion receptors, cell adhesion molecules, actin polymerization). (LLM, conf=0.76)
- Not checked yetcites [41] Tomimatsu Y, Idemoto S, Moriguchi S, Watanabe S, Nakanishi H. Proteases involved in long-term potentiation. Life Sci. 2002;72:355–361. doi: 10.1016/s0024-3205(02)02285-3. [DOI] [PubMed] [Google Scholar] source
- Not checked yetcites [42] Huttenlocher A, et al. Regulation of cell migration by the calcium-dependent protease calpain. J Biol Chem. 1997;272:32719–32722. doi: 10.1074/jbc.272.52.32719. [DOI] [PubMed] [Google Scholar] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Could not verify
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within-train facilitation of theta burst responses was not detectably different at the 10–20-min vs. 60–90-min delays”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, the same stimulation doubled the level of potentiation when delayed by 60 min (Fig. 1 A and B).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“TBS2 delivered 90 min after TBS1 resulted in the same degree of LTP as obtained with a 60-min delay (Fig. 1E).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Analyses of F-actin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were “missed” by the first stimulation bout.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Automated counting showed that TBS1 causes a marked increase in densely F-actin-positive spines that is of comparable size at 15 and 75 min after stimulation (Fig. 2 A and B).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“similarly, 1-min trains of 5-Hz pulses fully reversed LTP2 when delivered 60 s, but not 60 min, after TBS2 (Fig. 1F).”
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In the paper
“The induction probability was not dependent on the time that the slice was in the recording chamber (Fig. 3E, Right).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Spines that enlarged after glutamate uncaging were refractory to successive attempts at induction, even when the timing between uncaging events was extended beyond one hour (Fig. 3E, Left).”
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- Probably not a substantial claim. 14
- It may state two separate claims as one. 21
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This form of plasticity shares many properties with Schaffer collateral LTP, including dependence on N-methyl-d-aspartate receptors (NMDARs), Rho GTPase signaling, Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, F-actin polymerization and synaptic AMPAR insertion (20–24).”
What the sources say
- Partly supportedcites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceExperimental — accuracy not yet measured
The sections on crosstalk at nearby synapses and synaptically induced plasticity (pages unavailable) describe NMDA-receptor-mediated calcium signals and LTP induced by Schaffer collateral stimulation. The paper also links spine enlargement to AMPA-receptor number, but does not establish synaptic AMPAR insertion or dependence on Rho GTPase signaling, CaMKII phosphorylation, or F-actin polymerization. (LLM, conf=0.84)
- Partly supportedcites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceExperimental — accuracy not yet measured
The paper’s Abstract (page not provided) reports that single-spine enlargement depends on NMDA receptors and actin polymerization, that long-lasting enlargement requires CaMKII activity, and that AMPA-receptor-mediated currents increase at the stimulated spine. It does not establish dependence on Rho GTPase signaling or CaMKII phosphorylation, and increased AMPA currents do not by themselves demonstrate synaptic AMPAR insertion. (LLM, conf=0.87)
- Partly supportedcites [22] Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H. The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron. 2008;57:719–729. doi: 10.1016/j.neuron.2008.01.013. [DOI] [PubMed] [Google Scholar] sourceExperimental — accuracy not yet measured
The “Enlargement Pool of F-Actin in Dendritic Spines” and “The Stable Pool of F-Actin” sections (page not supplied) link spine enlargement and LTP to actin polymerization and report a role for CaMKII. They do not establish the claimed dependence on Rho GTPase signaling, CaMKII phosphorylation, or synaptic AMPAR insertion, or make the full comparison with Schaffer collateral LTP. (LLM, conf=0.87)
- Partly supportedcites [23] Makino H, Malinow R. AMPA receptor incorporation into synapses during LTP: The role of lateral movement and exocytosis. Neuron. 2009;64:381–390. doi: 10.1016/j.neuron.2009.08.035. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceExperimental — accuracy not yet measured
The Results section (‘Input-specific reduction of AMPAR mobility on spines following LTP’; page not provided) reports synaptic incorporation of GluR1-containing AMPARs and describes induction under conditions permitting NMDA receptor activation. It does not establish NMDAR dependence or address dependence on Rho GTPase signaling, CaMKII phosphorylation, or F-actin polymerization. (LLM, conf=0.86)
- Partly supportedcites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] sourceExperimental — accuracy not yet measured
The passage on NMDA-receptor and CaMKII inhibition (section labeled Abstract; page unavailable) supports dependence of single-spine enlargement and Rho GTPase activation on those pathways. The paper also links Rho GTPases to actin-cytoskeleton regulation, but the passages do not establish dependence on CaMKII phosphorylation, F-actin polymerization, or synaptic AMPAR insertion, nor do they directly compare all these properties with Schaffer collateral LTP. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A third train delayed by 60 min after TBS2 again increased potentiation, whereas a fourth and fifth had no effect (Fig. 1D).”
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TBS2 caused short-term, but not additional long-term, response facilitation when delivered at 10 or 30 min after TBS1.”
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Forty-minute treatments that immediately preceded TBS1, or that ended 10 min before the theta bursts, had no effect on baseline physiology or the induction of LTP1 (Fig. 4D, Left).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“However, as shown in Fig. 4D, brefeldin administered after TBS1 also produced a dramatic and unexpected result: it caused LTP1 to gradually decay back to baseline, again without affecting responses to a control input.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Head volume changes did not occur in neighboring spines, confirming that the stimulation protocol produces plasticity at a single synapse.”
boosteddirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, the enlargement probability was significantly greater in young than in adult slices (P < 0.005) even though the targeted spines were of similar volume and the same induction protocol was used (Fig. 3D).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Such an event would necessarily increase excitatory postsynaptic potentials (EPSPs) at 30–60 min after TBS1 and this is not observed.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Regarding the cellular bases for the distinction between low and high threshold spines, we found that brief treatments with a drug that selectively enhances AMPA receptor-gated synaptic currents markedly increases both the number of spines in which TBS1 triggers actin polymerization and the magnitude of LTP1.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Second, the glutamate-uncaging experiments were designed to produce maximal stimulation of NMDARs and yet detected two classes of spines in the proportions expected from the LTP studies.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Activity-dependent synaptic plasticity, and, in particular, long-term potentiation (LTP) of glutamatergic transmission, is thought to underlie rapid storage of new information (5, 6).”
What the sources say
- Not checked yetcites [5] Lynch G, Rex CS, Chen LY, Gall CM. Synaptic mechanisms for encoding memory. In: Koob G, Thompson RF, Le Moal M, editors. Encyclopedia of Behavioral Neuroscience. London: Academic; 2009. pp. 356–366. section ed Shors T. [Google Scholar]
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hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Other studies using variable stimulation intensities suggest that additional potentiation can be induced four hours after induction of LTP1 (10, 12).”
What the sources say
- Not checked yetcites [10] Frey U, Morris RG. Synaptic tagging: Implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 1998;21:181–188. doi: 10.1016/s0166-2236(97)01189-2. [DOI] [PubMed] [Google Scholar] source
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hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Low-frequency (5-Hz) stimulation erases LTP1 if applied shortly after TBS but then becomes progressively less effective over the following 30 min (8, 14);”
What the sources say
- Not checked yetcites [8] Huang CC, Liang YC, Hsu KS. A role for extracellular adenosine in time-dependent reversal of long-term potentiation by low-frequency stimulation at hippocampal CA1 synapses. J Neurosci. 1999;19:9728–9738. doi: 10.1523/JNEUROSCI.19-22-09728.1999. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In all, the present results show that LTP has a previously undetected refractory period, lasting for 30–60 min, which creates an analog of the behavioral spaced trials effect (13).”
What the sources say
- Not checked yetcites [13] Anderson MJ, Jablonski SA, Klimas DB. Spaced initial stimulus familiarization enhances novelty preference in Long-Evans rats. Behav Processes. 2008;78:481–486. doi: 10.1016/j.beproc.2008.02.005. [DOI] [PubMed] [Google Scholar] source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The mechanism underlying this phenomenon involves local spreading of signaling cascades from the activated spine to its neighbors, and some of these spreading signals are potent drivers of F-actin dynamics (24–26).”
What the sources say
- Not checked yetcites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The spaced-trial effect operates across multiple time frames, ranging from a few seconds to weeks (30).”
What the sources say
- Not checked yetcites [30] Cepeda NJ, Pashler H, Vul E, Wixted JT, Rohrer D. Distributed practice in verbal recall tasks: A review and quantitative synthesis. Psychol Bull. 2006;132:354–380. doi: 10.1037/0033-2909.132.3.354. [DOI] [PubMed] [Google Scholar] source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Previous efforts to find neurobiological explanations for the advantages of distributed practice obtained evidence that spaced trials can offset memory defects in mice lacking two variants of the transcription factor CREB (31, 32).”
What the sources say
- Not checked yetcites [31] Kogan JH, et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol. 1997;7:1–11. doi: 10.1016/s0960-9822(06)00022-4. [DOI] [PubMed] [Google Scholar] source
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plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The latter finding points to a hypothesis in which similarly delayed events set in motion by TBS1 serve to anchor LTP in one set of spines and to provide ingredients needed for potentiation in a second.”
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The low success rate in adults was unlikely related to technical issues because we used a strong induction protocol (20) that caused structural plasticity in >80% of young spines (Fig. 3C), a value in good agreement with previous studies (20, 21).”
What the sources say
- Not checked yetcites [20] Harvey CD, Svoboda K. Locally dynamic synaptic learning rules in pyramidal neuron dendrites. Nature. 2007;450:1195–1200. doi: 10.1038/nature06416. [DOI] [PMC free article] [PubMed] [Google Scholar] source
- Not checked yetcites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and (ii) conversion of TBS1-resistant spines into the low threshold state, which provides a refreshed pool of synapses capable of responding to TBS2.”
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Precise alignment of the stimulation scanner to the image scanner was confirmed by ablation of a 0.5-μm tetraspec bead (Invitrogen) with a high-energy pulse of 720-nm light.”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“several studies have shown that the kinase PKMζ is engaged at ≥1 h after induction and then contributes to maintenance of LTP (39).”
What the sources say
- Not checked yetcites [39] Sacktor TC. PKMzeta, LTP maintenance, and the dynamic molecular biology of memory storage. Prog Brain Res. 2008;169:27–40. doi: 10.1016/S0079-6123(07)00002-7. [DOI] [PubMed] [Google Scholar] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“One aspect of our data links the requirement for long delays to machinery that also serves to stabilize previously induced LTP and, thereby, supports consolidation explanations (43) for the behavioral effects.”
What the sources say
- Not checked yetcites [43] Glenberg AM. Component-levels theory of the effects of spacing of repetitions on recall and recognition. Mem Cognit. 1979;7:95–112. doi: 10.3758/bf03197590. [DOI] [PubMed] [Google Scholar] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Prior work suggesting that strong stimulation of single synapses causes the spread of active GTPases to neighboring spines (24, 25) is of interest in this regard because these enzymes play critical roles in the production of stable LTP.”
What the sources say
- Not checked yetcites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“because these enzymes play critical roles in the production of stable LTP.”
- Also stated in: § Discussion · plain
“spines (24, 25) is of interest in this regard because these enzymes play critical roles in the production of stable LTP.”
What the sources say
- Not checked yetcites [24] Murakoshi H, Wang H, Yasuda R. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 2011;472:100–104. doi: 10.1038/nature09823. [DOI] [PMC free article] [PubMed] [Google Scholar] source
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plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Discussion · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, it implies that the delayed membrane insertion step indicated by the brefeldin experiments involves delivery of AMPA receptors to synapses.”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“This threshold was chosen before the experiments were conducted and was based on prior studies (21).”
What the sources say
- Not checked yetcites [21] Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H. Structural basis of long-term potentiation in single dendritic spines. Nature. 2004;429:761–766. doi: 10.1038/nature02617. [DOI] [PMC free article] [PubMed] [Google Scholar] source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Volume changes at nearby spines were also analyzed to ensure that laser targeting of individual spines was specific.”
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, previously undetected cellular mechanisms impose temporal spacing requirements for synaptic plasticity and, thereby, provide a neurobiological explanation for one temporal segment of a ubiquitous feature of learning.”
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Reports that induction of LTP is accompanied by prolonged activation of CaMKII (38), a kinase localized to synapses, suggest a candidate for this role.”
What the sources say
- Not checked yetcites [38] Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002;3:175–190. doi: 10.1038/nrn753. [DOI] [PubMed] [Google Scholar] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The spine threshold component of the present results implies that spaced trials capture a greater percentage of the information carried by activated afferent systems, something that would allow for easier cue recognition during retention tests.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The authors state this as an assumption.
The priming effect of TBS1 on nonresponsive spines occurs at a stage located between the transmitter receptors and the multiple steps leading to the assembly and stabilization of actin filaments.
“We, therefore, assume that the priming effect of TBS1 on nonresponsive spines occurs at a stage located between the transmitter receptors and the multiple steps leading to the assembly and stabilization of actin filaments.”
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?
In the citing paper
“However, for longer intervals (60 or 90 minutes), a cumulative increase in LTP was observed over three bursts of stimulation.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In the citing paper
“Theta-burst stimuli applied at intervals of 10 or 40 minutes did not cumulatively increase LTP.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In the citing paper
“The second theta-burst stimulus yielded polymerization in spines that were not apparently affected by the first stimulus, if the second followed the first by 60 or 90 minutes.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In the citing paper
“This 60-minute interval was predicted to be optimal for learning because stimuli separated by 60 minutes had previously been found to enhance LTP in wild-type rodents47.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In the citing paper
“For the spaced LTP protocol of Gall, Lynch and colleagues47,48, an interval of 40–60 minutes is needed for successive theta-burst stimuli to further increase LTP.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In the citing paper
“Kramár et al.47 noted that in hippocampal slices, additional potentiation can be induced up to 4 hours after induction of the first LTP increment81.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
In the citing paper
“The required refractory period of ~1 hour between successive theta-burst stimuli to induce progressive increments in hippocampal LTP46,47 may be in line with the first of these variants, which is that short intervals are insufficient for consolidation and consequent summation of memory traces.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [47]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Discussion
“Previous efforts to find neurobiological explanations for the advantages of distributed practice obtained evidence that spaced trials can offset memory defects in mice lacking two variants of the transcription factor CREB (31, 32).”
§ References
“32.Yin JC, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila.”
Citations
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Metadata
- Authors
- Kramár, E. A., Babayan, A. H., Gavin, C. F., Cox, C. D., Jafari, M., Gall, C. M., Rumbaugh, G., & Lynch, G.
- Affiliations
- Departments of aAnatomy and Neurobiology and
- Scripps Research Institute (US)
- University of California, Irvine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-03-12
- Volume
- 109
- Issue
- 13
- Pages
- 5121-5126
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3323981
- OpenAlex
- W1998698062
- Cited by
- 192
- References
- 49
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 24 · 2023: 17 · 2022: 8 · 2021: 13 · 2020: 15 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 10 · 2012: 4
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH083346)
- National Institute of Neurological Disorders and Stroke (P01NS045260, NS045260, R01NS064079, NS064079)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- spaced learning, massed training, long-term potentiation, theta burst stimulation, hippocampal CA1, synaptic plasticity, glutamate uncaging, synaptic variability, membrane insertion
- MeSH terms
- Actins, Animals, Learning, Male, Mice, Inbred C57BL, Synaptic Transmission, Synapses, Theta Rhythm, Time Factors, Rats, Sprague-Dawley, Long-Term Potentiation, Dendritic Spines, Mice, Rats, Polymerization, In Vitro Techniques
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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.
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