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The DOI matches its Crossref record; 109 of the 110 references it cites were found in a registry or an index, and 1 are not checked yet; 33 of the 44 sources its claims cite were checked for support.

PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity

Open access
Rivero-Ríos, Pilar, Uygun, Tunahan, Chavis, Garrett D., Lee, Hankyu, Duan, Bo, Sutton, Michael A., Weisman, Lois S.·2025·Journal of Cell Biology
DOI 10.1083/jcb.202411198PMC PMC12494181
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Abstract

Two major protein recycling pathways have emerged as key regulators of enduring forms of synaptic plasticity, such as long-term potentiation (LTP), yet how these pathways are recruited during plasticity is unknown. Phosphatidylinositol-3-phosphate (PI(3)P) is a key regulator of endosomal trafficking and alterations in this lipid have been linked to neurodegeneration. Here, using primary hippocampal neurons, we demonstrate dynamic PI(3)P synthesis during chemical induction of LTP (cLTP), which drives coordinate recruitment of the SNX17–Retriever and SNX27–Retromer pathways to endosomes and synaptic sites. Both pathways are necessary for the cLTP-dependent structural enlargement of dendritic spines and act in parallel by recycling distinct sets of cell surface proteins at synapses. Importantly, preventing PI(3)P synthesis blocks synaptic recruitment of SNX17 and SNX27, decreases cargo recycling, and blocks LTP in cultured neurons and hippocampal slices. These findings provide mechanistic insights into the regulation of endocytic recycling at synapses and define a role for dynamic PI(3)P synthesis in synaptic plasticity.

Verified 2026-11-08 · 1 reference not checked yet

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

PI(3)P synthesis increases during chemical LTP and coordinates the SNX17-Retriever and SNX27-Retromer recycling pathways to support dendritic spine structural plasticity. Blocking VPS34-dependent PI(3)P production prevents SNX17/SNX27 recruitment, reduces recycling of β1-integrin and GluA1, and impairs LTP.

Key findings

  • cLTP rapidly increases dendritic PI(3)P-positive puncta; VPS34 inhibitors VPS34-IN1 and SAR405 reduced PI(3)P puncta by approximately 72% and 85%, respectively.
  • PI(3)P synthesis is required for LTP and structural plasticity: VPS34-IN1 impaired LTP in acute hippocampal slices, and VPS34 inhibition or VPS34 knockdown blocked cLTP-dependent increases in dendritic spine width.
  • SNX17 and SNX27 are coordinately recruited to PI(3)P-positive endosomes and dendritic spines after cLTP; approximately 80% of SNX17- or SNX27-positive puncta overlapped with PI(3)P, and approximately 70% of SNX17/SNX27-positive endosomes contained VPS34.
  • SNX17 and SNX27 act in parallel on distinct cargoes: SNX17 knockdown reduced surface β1-integrin but not GluA1, while SNX27 knockdown reduced surface GluA1 but not β1-integrin; VPS34-shRNA reduced surface β1-integrin by approximately 42.6% and surface GluA1 by approximately 47.8%.

Methods

  • Primary rat hippocampal and cortical neurons from postnatal day 1–2 pups of either sex, plus acute hippocampal slices from 6–8-week-old wild-type mice; cLTP was induced with 400 μM glycine in Mg2+-free HBS for 5 min.
  • Live-cell and fixed confocal imaging, colocalization analysis in ImageJ, surface biotinylation, immunoprecipitation, Western blotting, shRNA knockdown/rescue, and electrophysiological fEPSP recordings in CA1 with two 100 Hz, 1 s high-frequency stimulations separated by 30 s.
  • Data are means ± SEM; comparisons used unpaired two-tailed Student’s t test, one-way ANOVA with Tukey’s post hoc, or two-way ANOVA with Sidak’s multiple comparison test.

Limitations

  • The paper states that the mechanism underlying VPS34 activation and endosomal recruitment remains unclear; no significant change in VPS34 phosphorylation was detected after cLTP, suggesting indirect regulation via interacting partners or upstream regulators.
  • The paper notes that additional PI(3)P effectors and recycling pathways may contribute, most neuronal SNX17 cargoes remain unidentified, and roles for candidates such as PIKfyve in LTP have yet to be explored.
  • Evident from the text: several key imaging experiments rely on tagged or overexpressed SNX17/SNX27 and VPS34 constructs because suitable antibodies for endogenous rat VPS34 or SNX27 were unavailable; cLTP is a chemical induction protocol rather than physiological synaptic stimulation, and data distribution was assumed normal but not formally tested.

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

Integrity signals

Registry

Crossref · 10.1083/jcb.202411198

Cites

109 of 110 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

33 of 44 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation

    The addition of an N-terminal tag to SNX17 and SNX27 does not interfere with their ability to bind cargo or endosomal membranes.

    “Note that the addition of an N-terminal tag to these proteins does not interfere with their ability to bind cargo or endosomal membranes”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites McNally et al., 2017 source

      The Results section on proteomic identification reports that N-terminally GFP-tagged SNX17 localized to early endosomes and bound the cargo LRP1. Our copy does not show that an N-terminal tag likewise preserves SNX27’s cargo binding or endosomal localization, so the claim is supported for SNX17 but not SNX27. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites McMillan et al., 2021 source

      In Results (‘A neuronal SNX27 interactome’), the paper reports that GFP-SNX27 retained endosomal localisation. The Results figure caption (‘LRFNs interact with SNX27’) also reports an interaction between GFP-SNX27 and LRFN2. These findings support retained activity for tagged SNX27, but the paper does not establish the same for tagged SNX17. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Neuronal SNX27 cargoes include AMPA-type glutamate receptors.

    “Neuronal SNX27 cargoes include key receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type glutamate receptors”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Loo et al., 2014 source
    • cites McMillan et al., 2021 source
  • Premisecitation

    In neurons, the SNX17-Retriever pathway plays a key role in regulating synapse function and plasticity.

    “in neurons, this pathway also plays a key role in regulating synapse function and plasticity”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rivero-Ríos et al., 2023 source
  • Premisecitation

    Both SNX17 and SNX27 can interact with PI(3)P through their PX domains.

    “both interact with the signaling lipid PI(3)P via their PX domains”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Knauth et al., 2005 source
    • cites Lunn et al., 2007 source
    • cites Gillooly et al., 2000 source

      The Introduction says PI(3)P binds proteins with FYVE domains, and the Discussion describes PI(3)P binding by EEA1. Searches for SNX17, SNX27, sorting nexins, and PX-domain binding found no passage addressing whether either protein interacts with PI(3)P through a PX domain. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Premisecitation

    The role of SNX17 in LTP is mediated, at least in part, by promoting the recycling of the adhesion protein β1-integrin.

    “our findings show that the role of SNX17 in LTP is mediated, at least in part, by promoting the recycling of the adhesion protein β1-integrin”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rivero-Ríos et al., 2023 source
  • Probably not a substantial claim. 30
  • It may state two separate claims as one. 25

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Much of what is known about endocytic recycling in neurons has come from studies focused on the SNX27-Retromer pathway.

    “Much of what we know about endocytic recycling in neurons has come from studies focused on the SNX27-Retromer pathway”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Wang et al., 2013 source

      The Results show that SNX27 affects glutamate-receptor recycling, including in primary neurons. But the Discussion says whether this recycling depends on retromer remains to be investigated; it also does not establish the broader claim that much of what is known about neuronal endocytic recycling comes from studies of that pathway. No page numbers are available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Hussain et al., 2014 source

      The Discussion reports that SNX27 binds AMPA receptors and facilitates their trafficking to the neuronal surface, so this is a study of SNX27-related endocytic recycling. It does not establish that much of what is known about neuronal endocytic recycling comes from SNX27–Retromer studies, nor does it directly examine the combined pathway. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Loo et al., 2014 source

      The Discussion (page unavailable) says that several studies established SNX27’s importance in endosome-to-plasma-membrane trafficking, and the Results show that SNX27 loss impairs recycling in neurons. The paper mentions retromer cargoes, but it does not establish that much of what is known about neuronal endocytic recycling comes from studies focused on the SNX27–retromer pathway. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Chronic defects in PI(3)P synthesis are linked to reductions in dendritic spine density, reactive gliosis, and progressive neurodegeneration.

    “Chronic defects in PI(3)P synthesis are linked to reductions in dendritic spine density, reactive gliosis, and progressive neurodegeneration”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Wang et al., 2011 source
    • cites Zhou et al., 2010 source

      The Results report that Pik3c3 deletion depleted PI3P and caused progressive degeneration of sensory neurons, but describe that degeneration as rapid, occurring within days. The paper does not report reduced dendritic spine density. Its observation of activated astrocytes and microglia concerns aged Atg7-deficient mice, not the Pik3c3-deficient mice used to study PI3P depletion. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    SNX27 is required for LTP, and alterations in this pathway prevent cLTP by impairing the activity-dependent recruitment of surface AMPA receptors.

    “Similar to SNX17, SNX27 is also required for LTP. Alterations in this pathway prevent cLTP by impairing the activity-dependent recruitment of surface AMPA receptors”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Hussain et al., 2014 source

      The Results report that SNX27 depletion completely blocked the cLTP-induced increase in surface GluA1, supporting the claim about impaired activity-dependent AMPAR recruitment. The paper used chemical stimulation to mimic LTP and measured receptor surface expression; it does not show that SNX27 loss prevents LTP or cLTP itself. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Loo et al., 2014 source

      The Results section reports that SNX27 knockout abolished LTP in hippocampal slices and that glycine-induced stimulation barely increased surface GluA1 in knockout neurons. The paper does not directly show that chemical LTP itself was prevented: it measured receptor insertion after chemical stimulation, while the abolished LTP response was measured in slices using electrical stimulation. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Temkin et al., 2017 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    PI(3)P is predominantly localized on early endosomes and functions by recruiting effectors that contain PX and FYVE domains.

    “PI(3)P is predominantly localized on early endosomes and functions by recruiting a variety of effectors that contain PI(3)P-binding domains, such as PX (Phox homology) and FYVE (Fab1, YOTB, Vac1, EEA1) domains”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Marat and Haucke, 2016 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Multiple types of proteins undergo rapid externalization in response to cLTP.

    “A recent quantitative analysis of the neuronal surface proteome demonstrated that multiple types of proteins undergo rapid externalization in response to cLTP (van Oostrum et al., 2020).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites van Oostrum et al., 2020 source

  • Probably not a substantial claim.

    Premisecitation

    Extensive changes in the neuronal surface proteome upon cLTP are mediated by the delivery of membrane proteins from intracellular compartments.

    “recent findings that show extensive changes in the neuronal surface proteome upon cLTP, which are mediated by the delivery of membrane proteins from intracellular compartments”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites van Oostrum et al., 2020 source

      The Results section (‘Surface trafficking of diverse cargo during cLTP,’ Fig. 6) reports extensive surface-protein changes and says the increased surface abundance of AMPA receptors indicates exocytosis. It does not establish that delivery from intracellular compartments mediates the broader set of changes; the Discussion says the other proteins with increased surface abundance *could* account for the role of exocytosis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    PI(3)P plays key roles in neurotransmission by regulating synaptic vesicle cycling.

    “PI(3)P plays key roles in neurotransmission by regulating synaptic vesicle cycling”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Liu et al., 2022 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In neurons, PI(3)P is widely distributed in dendrites and axons, enriched at synapses, and co-localizes with PSD95.

    “In neurons, PI(3)P is widely distributed in both dendrites and axons, with an enrichment at synapses, where it co-localizes with the postsynaptic scaffold PSD95”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wang et al., 2011 source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    β1-integrin localizes to postsynaptic sites in hippocampal neurons and influences cytoskeletal organization, dendritic spine maturation, and synaptic transmission.

    “It localizes to postsynaptic sites in hippocampal neurons and influences cytoskeletal organization, dendritic spine maturation, and synaptic transmission”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Babayan et al., 2012 source

      The section ‘Induction of LTP triggers integrin activation and signaling’ (page unavailable) shows activated β1-integrin at PSD-95-positive hippocampal synapses. The Discussion (page unavailable) links integrins to actin organization and LTP, supporting an influence on synaptic plasticity. The copy does not establish an effect on dendritic spine maturation, and its evidence for synaptic transmission is more specific to potentiated responses than the claim suggests. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Bourgin et al., 2007 source

      The Discussion (page unavailable) places β1-integrin in dendritic spines of cultured hippocampal neurons and links β1-containing integrins to spine remodeling. It also associates integrin inactivation with defects in actin polymerization and synaptic plasticity, but treats an effect of the resulting spine-shape changes on synaptic transmission as a question for future study. Thus the claim's unqualified assertion about synaptic transmission goes beyond what this paper establishes. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Chan et al., 2006 source

      The Introduction reports impaired hippocampal AMPA receptor-dependent synaptic transmission after β1-integrin knockout, and the Discussion proposes a possible link between integrins and the actin cytoskeleton. The Introduction says many integrins localize to synapses, but does not establish that β1-integrin localizes specifically to postsynaptic sites. The paper does not show that β1-integrin influences dendritic spine maturation; its synaptic-structure results report no detectable morphological differences in axospinous contacts between knockout and control mice (page numbers unavailable in our copy). (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    A distinct, parallel SNX17-Retriever recycling pathway was recently discovered in non-neuronal cells.

    “A distinct, parallel SNX17-Retriever recycling pathway was recently discovered in non-neuronal cells”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites McNally et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    SNX17-dependent recycling requires the Retriever complex, the CCC complex, and the actin-regulatory WASH complex.

    “SNX17-dependent recycling requires the Retriever complex (VPS35L, VPS26C, and VPS29), the CCC complex (COMMD/CCDC22/CCDC93), and the actin-regulatory WASH complex”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Chen et al., 2019 source
    • cites McNally and Cullen, 2018 source
    • cites Simonetti and Cullen, 2019 source

      The Introduction (p. 3) identifies Retriever and CCC as regulators of SNX17-associated cargo recycling, and Figure 2 (p. 21) says Retriever binds SNX17 and associates with CCC and WASH. The paper describes these relationships but does not establish that all three complexes are required for SNX17-dependent recycling; Figure 2 also names two Retriever subunits as C16orf62 and DSCR3 rather than the aliases in the citing sentence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    AMPA receptors are rapidly inserted into the postsynaptic membrane in response to synaptic activity, a process critical for long-term potentiation.

    “AMPA receptors are rapidly inserted into the postsynaptic membrane in response to synaptic activity, a process critical for long-term potentiation”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Buonarati et al., 2019 source

      The Introduction’s “Secretory trafficking of AMPARs” section says stimulated exocytosis and subsequent surface diffusion increase synaptic AMPAR content during LTP. But “Regulation of postsynaptic AMPAR content” distinguishes the phases: the first 2–3 minutes depend on lateral diffusion, not acute exocytosis, which contributes later. Thus the claim captures activity-dependent receptor recruitment but overstates rapid insertion directly into the postsynaptic membrane. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Approximately 60-70% of the PI(3)P pool is produced by the lipid kinase VPS34.

    “Approximately 60–70% of the PI(3)P pool is produced by the lipid kinase VPS34”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Devereaux et al., 2013 source

      The Results section (“Steady-state and starvation-induced PI3P detected in Vps34 KO MEFs”) reports a ~65% decrease in PI3P after Vps34 knockout, supporting the stated range. The authors limit that conclusion to their mouse embryonic fibroblasts; the claim leaves the cell type unspecified and thus implies a more general PI3P pool than the experiment establishes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Ikonomov et al., 2015 source

      Results §3.4 reports that PtdIns3P fell to about 45% of control levels in Vps34-knockout podocytes. It also says the residual level was overestimated by roughly 20–25%, making a Vps34 contribution of approximately 60–70% plausible after correction. The estimate is supported for the podocytes studied, but the citing sentence presents it as an unqualified proportion of the PI(3)P pool. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    SNX27 regulates cargo recycling by engaging with the Retromer complex, a SNX-BAR dimer, and the WASH complex.

    “SNX27 regulates cargo recycling by engaging with the Retromer complex (VPS35, VPS26A/B, and VPS29), a SNX–Bin/Amphiphysin/Rvs (BAR) dimer (SNX1/2 in complex with SNX5/6), and the WASH complex”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Steinberg et al., 2013 source
    • cites Gallon et al., 2014 source

      The Abstract and Results establish that SNX27 engages the VPS26A or VPS26B subunit of retromer to regulate cargo recycling. The Discussion identifies WASH as a retromer interactor, but does not establish direct engagement between SNX27 and WASH; our copy also does not establish engagement with the specified SNX-BAR dimer. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Harbour et al., 2012 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    The VPS26C shRNA clone had been previously validated.

    “we utilized shRNA clones to knock down the Retriever subunit VPS26C, which we had previously validated”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Rivero-Ríos et al., 2023 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In non-neuronal cells, SNX17 defines a major endomembrane recycling pathway responsible for recycling over 120 cell-surface proteins from endosomes to the plasma membrane.

    “In non-neuronal cells, SNX17 defines a major endomembrane recycling pathway responsible for the recycling of over 120 cell-surface proteins from endosomes to the plasma membrane.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites McNally et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The VPS34 complex is regulated by post-translational modifications (PTMs), including phosphorylation.

    “Notably, the VPS34 complex is regulated by post-translational modifications (PTMs), including phosphorylation (Ohashi et al., 2019).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Ohashi et al., 2019 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingcitation

    A similar PI(3)P distribution in neurons was observed using the recombinant 2xFYVE domain of Hrs.

    “A similar PI(3)P distribution in neurons was observed using the recombinant 2xFYVE domain of Hrs”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Expression of CaMKII-T286D was sufficient to promote the formation of mScarlet-SNX27-positive puncta and their subsequent recruitment to dendritic spines.

    “the expression of CaMKII-T286D was sufficient to promote the formation of mScarlet-SNX27-positive puncta and their subsequent recruitment to dendritic spines”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The intensity of mScarlet-SNX27 at dendritic spines significantly increased 5 min after the stimulus, continued to rise at 10 min, and remained significantly elevated at all subsequent time points up to 30 min post-cLTP.

    “The intensity of mScarlet-SNX27 at dendritic spines significantly increased 5 min after the stimulus, continued to rise at 10 min, and remained significantly elevated at all subsequent time points up to 30 min post-cLTP”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Transient transfection of shRNA-resistant GFP-SNX17 in cultured neurons rescued the defects in dendritic spine enlargement following LTP caused by SNX17 knockdown, but not by SNX27 knockdown.

    “Importantly, transient transfection of shRNA-resistant GFP-SNX17 in cultured neurons rescued the defects in dendritic spine enlargement following LTP caused by SNX17 knockdown (Fig. 6A), but not by SNX27 knockdown”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    shRNA-resistant GFP-SNX27 rescued the defects in cLTP-induced spine enlargement resulting from SNX27 knockdown, but not those from SNX17 knockdown.

    “Conversely, shRNA-resistant GFP-SNX27 rescued the defects in cLTP-induced spine enlargement resulting from SNX27 knockdown (Fig. 6B), but not those from SNX17 knockdown”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS34-IN1 treatment significantly reduced the numbers of SNX17- and SNX27-positive puncta and blocked the cLTP-dependent increase in puncta numbers.

    “VPS34-IN1 treatment significantly reduced the numbers of SNX17- and SNX27- positive puncta and also blocked the cLTP-dependent increase in puncta numbers”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    SNX27-R restored cLTP-induced structural plasticity only in DMSO-treated cells, but not when VPS34 was inhibited.

    “Similarly, SNX27-R restored cLTP-induced structural plasticity only in DMSO-treated cells, but not when VPS34 was inhibited”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    cLTP promotes the recruitment of VPS34 to endosomal compartments, where it drives activity-dependent PI(3)P synthesis.

    “Our data indicate that cLTP promotes the recruitment of VPS34 to endosomal compartments, where it drives activity-dependent PI(3)P synthesis.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The numbers of dsRed-FYVE-positive puncta began increasing immediately after the cLTP stimulus and remained significantly elevated throughout the remaining time points analyzed, up to 30 min post-cLTP.

    “By contrast, the numbers of dsRed-FYVE- positive puncta began increasing immediately after the cLTP stimulus and remained significantly elevated throughout the remaining time points analyzed, up to 30 min post-cLTP.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in the number of PI(3)P-positive puncta reflect changes in PI(3)P synthesis.

  • It may state two separate claims as one.

    Findingown data

    cLTP led to a significant increase in PI(3)P puncta over time, which corresponded with a similar increase in GFP-SNX17 puncta.

    “We observed a significant increase in PI(3)P puncta over time (Fig. 3A,B), which corresponded with a similar increase in GFP-SNX17 puncta”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in the number of PI(3)P-positive puncta reflect changes in PI(3)P synthesis.

  • It may state two separate claims as one.

    Findingown data

    The numbers of GFP-SNX27-positive puncta increased upon cLTP and showed strong overlap with PI(3)P at each time point tested.

    “The numbers of GFP-SNX27- positive puncta also increased upon cLTP and showed strong overlap with PI(3)P at each time point tested”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Nifedipine, KT5720, and U0126 had no effect on the cLTP-dependent increase in VPS34 endosomes.

    “while the other inhibitors had no effect”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    The recombinant biosensor SNAP-FYVE-Hrs x2 confirmed the punctate distribution of PI(3)P along dendrites and its disappearance upon VPS34-IN1 treatment.

    “we also used a recently developed recombinant biosensor for PI(3)P, SNAP-FYVE-Hrs x 2 on fixed cells (Maib et al., 2024), which confirmed the punctate distribution of PI(3)P along dendrites and its disappearance upon VPS34-IN1 treatment”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    PI(3)P plays key roles in neurotransmission by regulating GABA receptor clustering at inhibitory synapses.

    “and GABA receptor clustering at inhibitory synapses”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Papadopoulos et al., 2017 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationown data

    Activity-dependent PI(3)P synthesis coordinates SNX17- and SNX27-dependent cargo recycling, which is crucial for the structural changes in dendritic spines necessary for enduring forms of synaptic plasticity.

    “Taken together, these studies demonstrate that activity-dependent PI(3)P synthesis coordinates SNX17- and SNX27- dependent cargo recycling, which is crucial for the structural changes in dendritic spines necessary for enduring forms of synaptic plasticity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Structural changes in dendritic spines are necessary for enduring forms of synaptic plasticity.
    • Rests on an assumption: cLTP-induced changes in cultured neurons reflect mechanisms of long-term potentiation in vivo.

  • It may state two separate claims as one.

    Interpretationreasoning

    SNX17 and SNX27 define two parallel endocytic recycling pathways that recycle different sets of cell surface proteins necessary for LTP.

    “SNX17 and SNX27 define two parallel endocytic recycling pathways that recycle different sets of cell surface proteins necessary for LTP.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    LTP engages both the SNX17 and SNX27 recycling pathways through a shared upstream regulator - the signaling lipid PI(3)P - which increases in response to synaptic NMDAR activation and downstream CaMKII signaling.

    “LTP engages both the SNX17 and SNX27 recycling pathways through a shared upstream regulator – the signaling lipid PI(3)P – which increases in response to synaptic NMDAR activation and downstream CaMKII signaling.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: cLTP-induced changes in cultured neurons reflect mechanisms of long-term potentiation in vivo.

  • Probably not a substantial claim.

    Premisecitation

    The recycling of AMPA-type glutamate receptors from endosomes to the plasma membrane is a well-established hallmark of LTP.

    “The recycling of AMPA-type glutamate receptors from endosomes to the plasma membrane is a well-established hallmark of LTP (Park, 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Park, 2018 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    The SNX27 PDZ domain directly interacts with C-terminal PDZ-binding motifs present in many neuronal surface proteins and is critical for the selective retrieval and recycling of SNX27-specific cargoes.

    “This unique PDZ domain directly interacts with C-terminal PDZ-binding motifs present in many neuronal surface proteins and is critical for the selective retrieval and recycling of SNX27-specific cargoes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Steinberg et al., 2013 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationown data

    Existing PI(3)P is sufficient to maintain endosomal pools of SNX17 and SNX27, but de novo PI(3)P synthesis following cLTP is required to drive their accumulation in spines.

    “suggesting that although existing PI(3)P is sufficient to maintain endosomal pools of SNX17 and SNX27, de novo PI(3)P synthesis following cLTP is required to drive their accumulation in spines.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Changes in the number of PI(3)P-positive puncta reflect changes in PI(3)P synthesis.

  • It may state two separate claims as one.

    Interpretationown data

    Both the SNX17-Retriever and SNX27-Retromer pathways are required for cLTP-related structural changes at spines, and each pathway is unable to compensate for the loss of the other.

    “These findings indicate that both the SNX17-Retriever and SNX27-Retromer pathways are required for the cLTP-related structural changes at spines, and that each pathway is unable to compensate for the loss of the other.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    The shRNA-resistant GFP-SNX27 (SNX27-R) was generated by introducing six silent mutations within the shRNA target sequence and its resistance to knockdown was validated in HEK293 cells.

    “For SNX27, we generated an shRNA-resistant GFP-SNX27 (SNX27-R) by introducing six silent mutations within the shRNA target sequence and validated its resistance to knockdown in HEK293 cells”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In cultured neurons, stimuli that induce LTP lead to an overall increase in the recycling of cargo and membrane components.

    “However, in cultured neurons, stimuli that induce LTP lead to an overall increase in the recycling of cargo and membrane components (Park et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Park et al., 2004 source

  • Probably not a substantial claim.

    Study design and conductcitation

    The shRNA-resistant GFP-SNX17 (SNX17-R) had been previously validated.

    “The shRNA-resistant GFP-SNX17 (SNX17-R) had been previously validated”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rivero-Ríos et al., 2023 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    SNX27 recycles more than 200 cell surface proteins in neurons.

    “Similarly, SNX27 recycles more than 200 cell surface proteins in neurons”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McMillan et al., 2021 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All experiments in the study were repeated at least three independent times.

    “All experiments were repeated at least three independent times.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    All steps of surface biotinylation were carried out at 4°C to prevent the internalization of the cell surface proteins.

    “All steps were carried out at 4°C to prevent the internalization of the cell surface proteins.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    To prepare representative images, the brightness and contrast were adjusted uniformly over all images of the respective assays.

    “To prepare representative images, the brightness and contrast were adjusted uniformly over all images of the respective assays using Photoshop 2021.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The knockdown efficiency for the SNX17, SNX27, VPS26B, VPS34, and Strumpellin shRNA clones in primary cortical neurons was tested.

    “To test the knockdown efficiency for the SNX17, SNX27, VPS26B, VPS34, and Strumpellin shRNA clones in primary cortical neurons, transduction-ready viral particles were produced by the University of Michigan Vector Core with a concentration of 107 transduction units per ml.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    The SNX17, SNX27, and VPS26B shRNA constructs and the shRNA-resistant SNX27 construct were validated.

    “Fig. S7 shows the validation of the SNX17-, SNX27-, and VPS26B- shRNA constructs, as well as the validation of the shRNA-resistant SNX27 construct.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The same laser settings and exposure times were used for the acquisition of individual experiments.

    “The same laser settings and exposure times were used for the acquisition of individual experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The identity of the constructs was verified by sequencing the entire coding region.

    “The identity of the constructs was verified by sequencing the entire coding region.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Dendritic spine width was quantified manually by an observer blind to the experimental conditions.

    “Dendritic spine width was quantified manually by an observer blind to the experimental conditions.”
    Quote in the paperNot a substantial claim
50 of 50

  • The paper relies on this without support.

    Changes in the number of PI(3)P-positive puncta reflect changes in PI(3)P synthesis.

    “we demonstrate dynamic PI(3)P synthesis during chemical induction of LTP (cLTP)”
    “the numbers of dsRed-FYVE- positive puncta began increasing immediately after the cLTP stimulus”

  • The paper relies on this without support.

    Changes in the number of VPS34-positive endosomes reflect changes in VPS34 localization to endosomes rather than changes in endosome number.

    “suggesting that it reflects changes in VPS34 localization.”

  • The paper relies on this without support.

    Structural changes in dendritic spines are necessary for enduring forms of synaptic plasticity.

    “which is crucial for the structural changes in dendritic spines necessary for enduring forms of synaptic plasticity.”

  • The paper relies on this without support.

    cLTP-induced changes in cultured neurons reflect mechanisms of long-term potentiation in vivo.

    “Chemical induction of LTP in hippocampal neurons was achieved via brief (5 min) exposure to a Mg2+- free HBS solution supplemented with: 0.4 mM Glycine (Thermo Fisher Scientific), 0.02 mM Bicuculline (Abcam), and 0.003 mM Strychnine (Tocris).”

  • The authors state this as an assumption.

    The data distribution was assumed to be normal, but this was not formally tested.

    “Data distribution was assumed to be normal, but this was not formally tested.”
5 of 5

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.

  • Slice orientation is described as both transverse and sagittal

    Major

    The slice-preparation method calls the hippocampal slices transverse, then states that they were cut sagittally.

  • SNX17 construct is described as containing SNX27

    Minor

    The stated source for the mNeonGreen-SNX17 construct is GFP-SNX17, but the amplified region is described as containing SNX27.

2 of 2

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1038/s41380-019-0364-x

    Major

    The cited work was retracted on 2022-10-18 (notice 10.1038/s41380-022-01814-1), before this paper was published (2025-09-08). Its authors could have known.

    Cited work 10.1038/s41380-019-0364-x · retracted 2022-10-18 · notice 10.1038/s41380-022-01814-1 · this paper published 2025-09-08

1 of 1

Citations

Cites

1 retracted

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Metadata

Authors
Rivero-Ríos, P., Uygun, T., Chavis, G. D., Lee, H., Duan, B., Sutton, M. A., & Weisman, L. S.
Affiliations
  • University of Michigan (US)
  • University of Michigan 6 Department of Molecular, Cellular, and Developmental Biology, , Ann Arbor, MI,
Corresponding author
  • Rivero-Ríos, Pilar
  • Sutton, Michael A.
  • Weisman, Lois S.
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2025-09-08
Volume
224
Issue
11
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.202411198
PMC
PMC12494181
OpenAlex
W4414061942
Cited by
1
References
109
Citations by year
2026: 1
FWCI
0.32
Type
journal article
Language
en
Open access
Licence
rupress.org/pages/terms102024 (vor)
Locations
  • The Journal of Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • National Institutes of Health (R01-NS129198, R01-NS097498, R01NS118769, R56DK139477)
  • Alzheimer’s Association Research Fellowship
  • University of Michigan
  • National Institute of Aging
  • Michigan Alzheimer’s Disease Research Center (P30AG072931)
  • University of Michigan Alzheimer’s Disease Center
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
phosphatidylinositol 3-phosphate, SNX17, SNX27, Retriever, retromer complex, endosomal recycling, synaptic plasticity, long-term potentiation, endocytic recycling, hippocampal neurons
MeSH terms
Animals, Cells, Cultured, Endocytosis, Hippocampus, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Endosomes, Synapses, Long-Term Potentiation, Phosphatidylinositol Phosphates, Dendritic Spines, Mice, Rats, Sorting Nexins

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.

A language model drew the claims from the paper on 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

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