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Cited by 60Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersCellular Mechanics and Interactions

State-dependent diffusion of actin-depolymerizing factor/cofilin underlies the enlargement and shrinkage of dendritic spines

Open access
Noguchi, Jun, Hayama, Tatsuya, Watanabe, Satoshi, Ucar, Hasan, Yagishita, Sho, Takahashi, Noriko, Kasai, Haruo·2016·Scientific Reports
DOI 10.1038/srep32897PMC PMC5011767
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Abstract

Dendritic spines are the postsynaptic sites of most excitatory synapses in the brain, and spine enlargement and shrinkage give rise to long-term potentiation and depression of synapses, respectively. Because spine structural plasticity is accompanied by remodeling of actin scaffolds, we hypothesized that the filamentous actin regulatory protein cofilin plays a crucial role in this process. Here we investigated the diffusional properties of cofilin, the actin-severing and depolymerizing actions of which are activated by dephosphorylation. Cofilin diffusion was measured using fluorescently labeled cofilin fusion proteins and two-photon imaging. We show that cofilins are highly diffusible along dendrites in the resting state. However, during spine enlargement, wild-type cofilin and a phosphomimetic cofilin mutant remain confined to the stimulated spine, whereas a nonphosphorylatable mutant does not. Moreover, inhibition of cofilin phosphorylation with a competitive peptide disables spine enlargement, suggesting that phosphorylated-cofilin accumulation is a key regulator of enlargement, which is localized to individual spines. Conversely, spine shrinkage spreads to neighboring spines, even though triggered by weaker stimuli than enlargement. Diffusion of exogenous cofilin injected into a pyramidal neuron soma causes spine shrinkage and reduced PSD95 in spines, suggesting that diffusion of dephosphorylated endogenous cofilin underlies the spreading of spine shrinkage and long-term depression.

AI snapshot

Written from the paper’s full text.

TL;DR

Cofilin diffusion is state-dependent: in resting dendrites WT/S3A cofilin are slowed by F-actin binding while S3E diffuses rapidly, but during spine enlargement WT and phosphomimetic S3E cofilin are confined to the stimulated spine whereas nonphosphorylatable S3A is not. Blocking cofilin phosphorylation impairs enlargement, while dephosphorylated cofilin diffusion/spread is linked to spine shrinkage and PSD95 reduction, suggesting p-cofilin supports confined enlargement and dp-cofilin mediates spreading shrinkage/LTD.

Key findings

  • In the resting state, WT cofilin diffused from the spine with a time constant of 41 ± 13 s, S3A with 21 ± 2.3 s, and S3E more rapidly with 5.4 ± 0.4 s (p < 0.0075), indicating WT/S3A diffusion was impeded by F-actin binding but all forms diffused quickly along dendrites.
  • During spine enlargement, WT and S3E PAGFP-cofilin accumulated in stimulated spines for 30 min, whereas S3A diffused rapidly from enlarged and resting spines; S3A in enlarged spines showed delayed diffusion (59 ± 8.4 s) versus no-uncage control (21 ± 2.3 s, p = 0.0024).
  • A dp-cofilin peptide that blocks endogenous cofilin phosphorylation greatly reduced spine enlargement in the early phase (1–2 min) and still reduced enlargement in the late phase (15–60 min).
  • LFS-induced spine shrinkage was accompanied by parallel PSD95 reduction and spread to neighboring spines within 3 μm at 60–80 min (p < 0.018); perfused dp-cofilin (10 μM) caused shrunken spines with reduced PSD95 at <150 μm from the soma, with larger reduction in proximal spines (40–130 μm) than distal spines (230–430 μm), while heat-inactivated cofilin did not.

Methods

  • Hippocampal slice cultures from 6- to 8-day-old Sprague Dawley rats were transfected with PAGFP-cofilin WT/S3A/S3E, mKeima, and PSD95-mGFP constructs, then imaged with two-photon microscopy, photoactivation, glutamate uncaging, and whole-cell patch-clamp perfusion.
  • Spine volumes were estimated from total fluorescence intensity; neighboring spines were defined as within 3 μm of stimulated spines unless otherwise stated; data are mean ± SEM, with Kruskal–Wallis/Steel, Mann–Whitney rank sum, and Wilcoxon signed-rank tests as indicated.

Limitations

  • The paper states that PAGFP-cofilin spread analysis could not be conducted during spine shrinkage because fluorescence background was high after long-term repetitive stimulation.
  • The paper states that enlargement was not completely abolished by the dp-cofilin peptide, likely due to either an incomplete peptide effect or a cofilin-phosphorylation-independent mechanism.
  • The text makes evident that data collection and analysis were not blinded, data were not randomized, and no statistical methods were used to predetermine sample sizes; the authors also describe some interpretations as speculative.

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

Integrity signals

Registry

Crossref · 10.1038/srep32897

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

16 of 33 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Interpretationown data

    The diffusion of WT and S3A cofilin, but not S3E cofilin, in the resting state was significantly impeded by their binding to F-actins.

    “These findings suggest that the diffusion of WT or S3A cofilin, but not S3E cofilin, was significantly impeded by their binding to F-actins1326.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Bernstein, B. W. & Bamburg, J. R. ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 20, 187–195 (2010). source

      The ‘Phosphorylation of Ser3’ section states that Ser3 phosphorylation inhibits cofilin binding to F-actin, and the pH-regulation section identifies S3A as a mutant that cannot be inactivated by phosphorylation (page numbers unavailable). These passages support the proposed binding distinction, but the paper does not report diffusion measurements or the claimed significant difference among WT, S3A and S3E cofilin in resting cells. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [26] Kiuchi, T., Ohashi, K., Kurita, S. & Mizuno, K. Cofilin promotes stimulus-induced lamellipodium formation by generating an abundant supply of actin monomers. J. Cell Biol. 177, 465–476 (2007). source

      The Results section, “Cofilin inactivation or knockdown markedly decreases the cytoplasmic actin monomer pool” (page unavailable), measures diffusion of photoactivated Dp-actin while cofilin variants are expressed—not diffusion of the cofilin variants themselves. Searches for cofilin diffusion and F-actin binding found no passage establishing that WT and S3A cofilin, but not S3E, have impeded diffusion in resting cells. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Findingown data

    WT and S3E PAGFP-cofilin accumulated in stimulated spines for 30 min after spine enlargement.

    “WT and the S3E PAGFP-cofilin mutant accumulated in the stimulated spines for 30 min after spine enlargement (Fig. 2A,E,G), similar to previous observations of the stable enlargement of the F-actin pool10.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Honkura, N., Matsuzaki, M., Noguchi, J., Ellis-Davies, G. C. & Kasai, H. The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57, 719–729 (2008). source
  • Premisecitation

    Changes in PSD are not proportionally induced during spine enlargement but occur after a delay of approximately 30 min.

    “In contrast, changes in PSD are not proportionally induced during spine enlargement but occur after a delay of approximately 30 min12.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Bosch, M. et al. Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron 82, 444–459 (2014). source

      The Results section on PSD growth reports that Homer1b and Shank1b did not increase during the first 45 minutes after sLTP induction and began increasing at about 60 minutes. This supports delayed, non-proportional PSD changes during initial spine enlargement, but not a delay of approximately 30 minutes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingown data

    Following dp-cofilin introduction, the reduction of PSD95-mGFP fluorescence was larger in proximal spines compared to distal spines or to the reduction caused by HI-cofilin.

    “Similarly, following dp-cofilin introduction, the reduction of PSD95-mGFP fluorescence was larger in the proximal spines compared to the reduction in distal spines or to the reduction caused by HI-cofilin (Fig. 4C).”
    Quote in the paperSubstantial claim
  • Findingown data

    At 10 s after photoactivation, PAGFP fluorescence in the irradiated spine was significantly smaller for S3E cofilin than for WT or S3A cofilin.

    “Thus, PAGFP fluorescence (FPAGFP) at 10 s after PA in the irradiated spine was significantly smaller for S3E mutants than for WT or S3A mutants (Fig. 1G).”
    Quote in the paperSubstantial claim
  • May combine two claims. 29
  • Classified as probably not a substantial claim. 12
  • The quote only partly states this claim. 1

  • May combine two claims.

    Interpretationown data

    Exogenous cofilins diffused along a dendrite and induced the spreading of spine shrinkage, similar to that induced by LFS or spike-timing dependent induction.

    “These experiments indicate that exogenous cofilins diffused along a dendrite and induced the spreading of spine shrinkage, similar to that induced by LFS (Supplementary Fig. S1) or spike-timing dependent induction9.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Hayama, T. et al. GABA promotes the competitive selection of dendritic spines by controlling local Ca2+ signaling. Nat Neurosci 16, 1409–1416 (2013). source
    • Rests on an assumption: Exogenous full-length recombinant dp-cofilin introduced into the soma and diffusing along dendrites mimics the behavior of endogenous dephosphorylated cofilin.
    • Rests on an assumption: Boiling at 95 °C for 15 min inactivates cofilin's spine-shrinking activity.

  • Classified as probably not a substantial claim.

    Premisecitation

    An accumulation of phosphorylated cofilin was reported after LTP stimulation using immunohistochemistry.

    “On the other hand, an accumulation of phosphorylated cofilin was reported after LTP stimulation using immunohistochemistry24.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Chen, L. Y., Rex, C. S., Casale, M. S., Gall, C. M. & Lynch, G. Changes in synaptic morphology accompany actin signaling during LTP. J. Neurosci. 27, 5363–5372 (2007). source

  • May combine two claims.

    Interpretationown data

    dp-cofilin efficiently diffused along dendrites, enabling heterosynaptic shrinkage of spines along dendrites.

    “Despite its binding to F-actins, we demonstrated that dp-cofilin efficiently diffused along dendrites, enabling heterosynaptic shrinkage of spines along dendrites, which was consistent with the spread of LTD along dendrites202122.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [20] Nishiyama, M., Hong, K., Mikoshiba, K., Poo, M. M. & Kato, K. Calcium stores regulate the polarity and input specificity of synaptic modification. Nature 408, 584–588 (2000). source
    • cites [21] Nishiyama, M., Togashi, K., Aihara, T. & Hong, K. GABAergic activities control spike timing- and frequency-dependent long-term depression at hippocampal excitatory synapses. Front. Synaptic Neurosci. 2, 22 (2010). source
    • cites [22] Wang, S. S., Khiroug, L. & Augustine, G. J. Quantification of spread of cerebellar long-term depression with chemical two-photon uncaging of glutamate. Proc. Natl. Acad. Sci. USA 97, 8635–8640 (2000). source
    • Rests on an assumption: Exogenous full-length recombinant dp-cofilin introduced into the soma and diffusing along dendrites mimics the behavior of endogenous dephosphorylated cofilin.

  • May combine two claims.

    Premisecitation

    Spine enlargement and LTP require stronger stimulation compared with spine shrinkage and LTD.

    “Spine enlargement and LTP require stronger stimulation compared with those for spine shrinkage and LTD.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [21] Nishiyama, M., Togashi, K., Aihara, T. & Hong, K. GABAergic activities control spike timing- and frequency-dependent long-term depression at hippocampal excitatory synapses. Front. Synaptic Neurosci. 2, 22 (2010). source

      The Results section on cooperative e-LTP (page unavailable) reports that LTP required co-activation of multiple inputs under the tested conditions, whereas LTD did not show that cooperative requirement. This supports a narrower difference in induction requirements, but the paper does not establish a general stronger-stimulation requirement or report spine enlargement and shrinkage. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [22] Wang, S. S., Khiroug, L. & Augustine, G. J. Quantification of spread of cerebellar long-term depression with chemical two-photon uncaging of glutamate. Proc. Natl. Acad. Sci. USA 97, 8635–8640 (2000). source

      The Results and Discussion describe the induction and spatial spread of cerebellar LTD, but do not compare stimulation requirements for LTP and LTD or for spine enlargement and shrinkage. Searches for those terms found no passage addressing the claimed comparison. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [23] Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993). source

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

    Premisecitation

    Cofilin accumulates during spine enlargement, and long-term spine enlargement is inhibited by shRNA-mediated cofilin knockdown.

    “Recently, cofilin has been shown to accumulate during spine enlargement, and long-term spine enlargement was inhibited by shRNA-mediated cofilin knockdown12.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Bosch, M. et al. Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron 82, 444–459 (2014). source

      The Results section reports that cofilin accumulated after sLTP induction and that spine enlargement was reduced at 20–30 minutes when shRNAs knocked down both cofilin and ADF. Crucially, cofilin-targeting shRNA alone did not produce that reduction, so the claim overstates what cofilin knockdown by itself achieved. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Both constitutively active and inactive-phosphomimetic cofilin mutants failed to resume long-term spine enlargement and cofilin accumulation.

    “Both constitutively active and inactive-phosphomimetic cofilin mutants failed to resume long-term spine enlargement and the cofilin accumulation12.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [12] Bosch, M. et al. Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron 82, 444–459 (2014). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Spine shrinkage tends to spread, as in LTD.

    “It has been reported that spine shrinkage tends to spread919 as in the case with LTD202122.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [9] Hayama, T. et al. GABA promotes the competitive selection of dendritic spines by controlling local Ca2+ signaling. Nat Neurosci 16, 1409–1416 (2013). source
    • cites [19] Wiegert, J. S. & Oertner, T. G. Long-term depression triggers the selective elimination of weakly integrated synapses. Proc Natl Acad Sci USA 110, E4510–E4519 (2013). source

      The Discussion reports that LTD induction destabilized stimulated spines and their neighbors, but says that depression of synaptic efficacy *might* have spread to neighboring synapses; it does not establish that LTD itself tends to spread. It also reports no immediate spine shrinkage under this study’s stimulation protocol. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [20] Nishiyama, M., Hong, K., Mikoshiba, K., Poo, M. M. & Kato, K. Calcium stores regulate the polarity and input specificity of synaptic modification. Nature 408, 584–588 (2000). source

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

    Premisecitation

    Cofilin is a highly abundant actin-regulatory protein that binds to and alters the physical properties of F-actin.

    “Cofilin is a highly abundant actin-regulatory protein, which binds to and alters the physical properties of F-actin1314.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [13] Bernstein, B. W. & Bamburg, J. R. ADF/cofilin: a functional node in cell biology. Trends Cell Biol. 20, 187–195 (2010). source

      The Modulation of actin dynamics section says cofilin regulates actin filaments and, when bound at high ratios, stabilizes F-actin in a twisted form. The Distribution section calls cofilin-1 the most ubiquitous form, but does not establish that cofilin is highly abundant; ubiquity is not the same as abundance. Page numbers are unavailable in our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [14] Hotulainen, P. et al. Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis. J Cell Biol 185, 323–339 (2009). source

      The Introduction says ADF/cofilins sever and depolymerize actin filaments, and the Discussion describes cofilin-1–induced filament disassembly. The Results report high cofilin-1 levels in the dendritic shaft, but do not establish that cofilin is highly abundant in general or specifically describe its binding to F-actin and alteration of its physical properties. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The early phase of spine enlargement was more potently blocked by dp-cofilin peptide than the late phase, which is opposite to the effect observed with an inhibitor or mutation of CaMKII.

    “The early phase appeared more potently blocked than the late phase, which is the opposite of the effect observed with an inhibitor or mutation of CaMKII47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47]

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

  • May combine two claims.

    Findingown data

    S3A cofilin diffusion from enlarged spines had a time constant of 59 ± 8.4 s, compared to 21 ± 2.3 s in the no-uncage control (p = 0.0024).

    “The slightly delayed S3A cofilin diffusion (Fig. 2E, orange square, time constant, 59 ± 8.4 s) compared to the ‘no uncage’ control (thin orange line, 21 ± 2.3 s, p = 0.0024, Mann–Whitney rank sum test) suggests that S3A cofilin was trapped in enlarged spines to some degree, likely by F-actin enrichment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Heat-inactivated cofilin did not detectably induce spine shrinkage or PSD95 reduction.

    “Moreover, heat-inactivated cofilin (HI-cofilin) did not detectably induce these effects (Fig. 4C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the resting state, wild-type cofilin diffused from the spine with a time constant of 41 ± 13 s, spread to neighboring spines, and was diluted along dendrites.

    “In the resting state, following PA, we found that wild-type (WT) cofilin diffused from the spine with a time constant of 41 ± 13 s, spread to neighboring spines, and was then diluted along dendrites (Fig. 1A,B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The dp-cofilin peptide greatly reduced spine enlargement in the early phase (1-2 min after stimulation) and still reduced enlargement during the late phase (15-60 min).

    “Spine enlargement was greatly reduced in the early phase (1–2 min after stimulation), and enlargement was still reduced during the late phase (15–60 min) (Fig. 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    S3A PAGFP-cofilin did not accumulate in stimulated spines and diffused more rapidly from both enlarged and resting spines.

    “In contrast, S3A PAGFP-cofilin more rapidly diffused from both the enlarged spine (Fig. 2A,E,G) and resting spines (Fig. 2E, orange thin line).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Low-frequency repetitive stimulation with glutamate uncaging (LFS; 1 Hz, 300 times) induced effective spine shrinkage accompanied by a parallel reduction in PSD95 fluorescence.

    “We found that effective spine shrinkage could be induced by LFS and was accompanied by a parallel reduction in PSD95 fluorescence (Supplementary Fig. S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Spine shrinkage spread to neighboring spines within 3 μm at 60-80 min after stimulation, but for neighbors further than 3 μm from the stimulated spine, the volume reduction was not significant.

    “At 60–80 min after stimulation, spine shrinkage of the stimulated spine (p < 0.018, Wilcoxon signed-rank test against zero) spread to neighboring spines within 3 μm, which was true for spine shrinkage that was induced by the spike-timing dependent protocol. However, for neighbors further than 3 μm from the stimulated spine, the volume reduction was not significant (Supplementary Fig. S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Cofilin diffusion along dendrites is state-dependent and tightly confined to the stimulated spine only when p-cofilin was induced by spine enlargement.

    “We investigated cofilin diffusion along dendrites and found that it was state-dependent and tightly confined to the stimulated spine only when p-cofilin was induced by spine enlargement.”
    • Also stated in: § Discussion · plain
      “Moreover, p-cofilin was confined to the spine only when the LTP induction protocol was applied.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Cofilin depolymerizes and cleaves F-actins.

    “Cofilin depolymerizes and cleaves F-actins15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Van Troys, M. et al. Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol 87, 649–667 (2008). source

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

    Study design and conductnone given

    Data collection and analysis were not performed in a blinded manner, and data were not randomized for analysis.

    “Data collection and analysis were not performed in a blinded manner, and data were not randomized for analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Low cofilin expression levels were used so as not to affect spine enlargement.

    “We used low cofilin expression levels so as not to affect spine enlargement, which was induced by repetitive glutamate uncaging in Mg2+-free solution (Fig. 2A–D).”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    Spines that changed volume >30% before uncaging were excluded from the data analysis.

    “Spines that changed volume >30% before uncaging were excluded from the data analysis4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004). source

  • May combine two claims.

    Interpretationreasoning

    Cofilin may impair and destabilize the critical F-actin that is polymerized at PSDs.

    “Thus, cofilin may impair and destabilize the critical F-actin that is polymerized at PSDs.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    No statistical methods were used to predetermine sample sizes, although the sample sizes are similar to those previously reported.

    “No statistical methods were used to predetermine sample sizes, although our sample sizes are similar to those previously reported45678.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 45678

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Spine enlargement is confined to the stimulated spine, as with LTP.

    “In contrast, spine enlargement is confined to the stimulated spine45678 as with LTP2123.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites 45678

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

    • cites [2123]

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

  • May combine two claims.

    Interpretationown data

    LTP stimulation phosphorylates cofilin and p-cofilin accumulates in stimulated spines.

    “Our data suggest that LTP stimulation phosphorylates cofilin and that p-cofilin accumulates in stimulated spines.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Cells with resting potentials at more than −53 mV at uncaging were excluded from data analyses.

    “Cells with resting potentials at more than −53 mV at uncaging were excluded from data analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Cofilin enlarges and shrinks spines, which is a very efficient mechanism for creating bidirectional structural plasticity.

    “Our data suggest that cofilin enlarges and shrinks spines, which is a very efficient mechanism for creating bidirectional structural plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dephosphorylated cofilin at serine-3 cleaves F-actin to generate new barbed ends and depolymerizes F-actin at its pointed end.

    “Dephosphorylated cofilin at its serine-3 residue (dp-cofilin) cleaves F-actin to generate new barbed ends that are sites for actin polymerization and depolymerizes F-actin at its pointed end to reduce fiber length.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Van Troys, M. et al. Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol 87, 649–667 (2008). source
    • cites [16] Tania, N., Prosk, E., Condeelis, J. & Edelstein-Keshet, L. A temporal model of cofilin regulation and the early peak of actin barbed ends in invasive tumor cells. Biophys J 100, 1883–1892 (2011). source

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

    Premisecitation

    The AMPA, but not NMDA, component of EPSPs is affected by LTP.

    “Consistently, the AMPA, but not NMDA, component of EPSPs is affected by LTP404142.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Kauer, J. A., Malenka, R. C. & Nicoll, R. A. A persistent postsynaptic modification mediates long-term potentiation in the hippocampus. Neuron 1, 911–917 (1988). source
    • cites [41] Muller, D. & Lynch, G. Long-term potentiation differentially affects two components of synaptic responses in hippocampus. Proc Natl Acad Sci USA 85, 9346–9350 (1988). source
    • cites [42] Asztely, F., Wigstrom, H. & Gustafsson, B. The Relative Contribution of NMDA Receptor Channels in the Expression of Long-term Potentiation in the Hippocampal CA1 Region. Eur J Neurosci 4, 681–690 (1992). source

  • May combine two claims.

    Premisecitation

    Phosphorylation of cofilin at serine-3 inhibits its actin-regulatory activities, and phosphorylated cofilin dissociates from F-actin.

    “These bidirectional enzymatic activities of cofilin are inhibited by its phosphorylation at the serine-3 residue, as phosphorylated cofilin (p-cofilin) dissociates from F-actin1516.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Van Troys, M. et al. Ins and outs of ADF/cofilin activity and regulation. Eur J Cell Biol 87, 649–667 (2008). source
    • cites [16] Tania, N., Prosk, E., Condeelis, J. & Edelstein-Keshet, L. A temporal model of cofilin regulation and the early peak of actin barbed ends in invasive tumor cells. Biophys J 100, 1883–1892 (2011). source

  • May combine two claims.

    Interpretationnone given

    p-cofilin (or dp-cofilin) generation naturally reduces dp-cofilin (or p-cofilin) and selectively induces either stimulated spine enlargement or shrinkage.

    “We propose that, firstly, p-cofilin (or dp-cofilin) generation naturally reduces dp-cofillin (or p-cofilin) and selectively induces either stimulated spine enlargement or shrinkage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cofilin phosphorylation and dephosphorylation are competitively induced, and once phosphorylation is induced by larger increases in cytosolic Ca2+ concentrations, cofilin is not dephosphorylated.

    “Thus, it is likely that cofilin phosphorylation and dephosphorylation are competitively induced, and once phosphorylation is induced by larger increases in cytosolic Ca2+ concentrations, cofilin is not dephosphorylated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The unexpected cofilin diffusional properties mediate an asymmetric organization of spine enlargement and shrinkage and play a key role in the efficient competitive selection of spines along dendrites.

    “Thus, the unexpected cofilin diffusional properties mediate an asymmetric organization of spine enlargement and shrinkage and play a key role in the efficient competitive selection of spines along dendrites.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    p- and dp-cofilin play roles in spine enlargement and shrinkage, respectively.

    “Our data support a role of p- and dp-cofilin in spine enlargement and shrinkage, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Synapses can communicate with each other by dp-cofilin diffusion and competition with p-cofilin, so that only spines that are more efficiently stimulated relative to neighboring spines can survive.

    “Thirdly, synapses can communicate with each other by dp-cofilin diffusion and competition with p-cofilin, so that only spines that are more efficiently stimulated relative to neighboring spines can survive.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Exogenous full-length recombinant dp-cofilin introduced into the soma and diffusing along dendrites mimics the behavior of endogenous dephosphorylated cofilin.
35 of 35

  • The paper relies on this without support.

    Exogenous full-length recombinant dp-cofilin introduced into the soma and diffusing along dendrites mimics the behavior of endogenous dephosphorylated cofilin.

    “Instead, we took advantage of whole-cell perfusion to introduce a dp-cofilin protein (full-length recombinant, 10 μM) into the soma of pyramidal neurons and investigated spines in the ternary dendrites, which were used in spine enlargement experiments.”
    “Thus, it is likely that the spreading of spine shrinkage is mediated by the cofilin diffusion.”

  • The paper relies on this without support.

    Boiling at 95 °C for 15 min inactivates cofilin's spine-shrinking activity.

    “Cofilin (HI-cofilin) was inactivated by boiling at 95 °C for 15 min.”
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Authors
Noguchi, J., Hayama, T., Watanabe, S., Ucar, H., Yagishita, S., Takahashi, N., & Kasai, H.
Affiliations
Japan Science and Technology Agency (JP)
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-09-06
Volume
6
Issue
1
Pages
32897-32897
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep32897
PMC
PMC5011767
OpenAlex
W2527653013
Semantic Scholar
1b7727c32969d9b60ddf38012db5630c38ae4d4e
Cited by
60
References
46
Citations by year
2026: 6 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 2 · 2016: 1
FWCI
2.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Japan Agency for Medical Research and Development
  • Ministry of Education, Culture, Sports, Science and Technology (26221001)
  • Japan Society for the Promotion of Science (26221001)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
cofilin, dendritic spines, actin depolymerization, cofilin phosphorylation, protein diffusion, long-term depression, long-term potentiation, PSD-95, synaptic plasticity, actin cytoskeleton remodeling
MeSH terms
Actins, Animals, Cerebrospinal Fluid, Female, Hippocampus, Male, Neuronal Plasticity, Neurons, Phosphorylation, Synapses, Rats, Sprague-Dawley, Long-Term Potentiation, Long-Term Synaptic Depression, Dendritic Spines, Actin Depolymerizing Factors, Destrin

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