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Cited by 3Neuroscience and Neuropharmacology ResearchCellular transport and secretionReceptor Mechanisms and Signaling

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index; none of the 51 sources its claims cite is checked for support yet.

Loss of SynDIG4/PRRT1 alters distribution of AMPA receptors in Rab4- and Rab11-positive endosomes and impairs basal AMPA receptor recycling

Open access
He, Chun-Wei, Díaz, Elva·2025·Frontiers in Pharmacology
DOI 10.3389/fphar.2025.1568908PMC PMC12133753

Published version of a preprint

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Abstract

The transmembrane protein Synapse Differentiation Induced Gene 4 (SynDIG4) functions as an auxiliary factor of AMPA receptors (AMPARs) and plays a critical role in excitatory synaptic plasticity as well as hippocampal-dependent learning and memory. Mice lacking SynDIG4 have reduced surface expression of GluA1 and GluA2 and are impaired in single tetanus-induced long-term potentiation and NMDA receptor (NMDAR)-dependent long-term depression. These findings suggest that SynDIG4 may play an important role in regulating AMPAR distribution through intracellular trafficking mechanisms; however, the precise roles by which SynDIG4 governs AMPAR distribution remain unclear. Here, we characterized the endocytosis and recycling of GluA1-containing AMPARs under basal conditions. We did not observe any change in baseline endocytosis; however, we did observe a significant decrease in recycling of GluA1-containing AMPARs in cultured hippocampal neurons from mice lacking SynDIG4. This resulted in a significant increase in the levels of internal GluA1 and GluA2, along with greater colocalization of these subunits with Rab4-positive recycling endosomes. Notably, the overlap between Rab4-positive and Rab11-positive vesicles was elevated in hippocampal neurons lacking SynDIG4, suggesting an impairment in the trafficking between these compartments. Furthermore, our findings revealed a reduction in surface GluA1 within synaptic regions of hippocampal neurons lacking SynDIG4. Collectively, these results indicate that SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions. This regulatory function of SynDIG4 may contribute to the deficits in GluA1-dependent synaptic plasticity and impairment of hippocampal-dependent behaviors observed in SynDIG4 deficient mice.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In SynDIG4/PRRT1 knockout hippocampal neurons, basal endocytosis of GluA1-containing AMPARs is unchanged, but recycling is reduced, causing intracellular accumulation of GluA1/GluA2 in Rab4-positive endosomes and increased Rab4-Rab11 overlap. SynDIG4 thus supports Rab4-dependent AMPAR recycling and synaptic surface GluA1 localization under baseline conditions.

Key findings

  • BS3 cross-linking in P14 acute slices showed increased intracellular-to-total GluA1 and GluA2 in SynDIG4 KO vs WT (ratio paired t-test; n = 3 biological replicates; *p < 0.05), while total GluA1, GluA2, and GluN1 levels and intracellular GluN1 were unchanged.
  • Antibody-feeding assays found comparable endocytosed GluA1 after 30 min, but reduced recycled GluA1 in SynDIG4 KO neurons (unpaired t-test; n = 15–20 images; *p < 0.05); >90% of endocytosed and recycled GluA1 colocalized with total GluA1 in both genotypes.
  • GluA1 and GluA2 colocalization with EEA1 and Rab11 was unchanged, but colocalization with Rab4 was significantly elevated in SynDIG4 KO neurons (Manders coefficient; n ≈ 40 dendrite stretches; p < 0.01, *p < 0.001). Rab4-Rab11 overlap was increased in KO neurons (p < 0.0001), Rab11 puncta size was increased, and Rab4/EEA1 puncta sizes and total Rab4/Rab11/EEA1 expression were unchanged.
  • STED microscopy showed reduced overlap of surface GluA1 puncta with PSD95 and reduced cross-correlation between sGluA1 and PSD95 in SynDIG4 KO neurons (n ≈ 40 dendrite stretches; *p < 0.05). SynDIG4 localized comparably to Rab4 and Rab11; ~25% localized to both compartments, 59.74% of Rab4-Rab11 colocalization sites contained SynDIG4, but only 12.63% of all SynDIG4 signals overlapped Rab4-Rab11 sites.

Methods

  • SynDIG4 KO mice on a C57BL/6J background; littermates of both sexes used. Primary hippocampal neurons from P0–P2 mice were cultured to DIV18–22; acute coronal brain slices were prepared from P14 mice.
  • Surface/intracellular AMPAR pools were assessed by BS3 cross-linking plus immunoblotting, immunofluorescence with surface or standard labeling, and antibody-feeding assays using GluA1-N/GluA2-N antibodies, Fab blocking, and dynasore (80 μM) to inhibit endocytosis during recycling. Imaging used confocal and STED microscopy.
  • Analysis included integrated density, puncta size, Manders colocalization via JaCoP, Pearson/Van Steensel analysis, and cross-correlation confidence analysis in FIJI/ImageJ; statistics used GraphPad Prism 10.3.1.

Limitations

  • Stated by the paper: the authors cannot exclude that SynDIG4 also contributes to AMPAR recycling via direct Rab4-to-plasma-membrane transport or other mechanisms, or that trafficking shifts pathways in KO neurons; SynDIG4 may regulate GluA1- and GluA2-containing AMPARs differently; STED vs confocal and PSD95 vs vGLUT1 comparisons should be interpreted cautiously; endocytosis relative to the available surface pool may occur more frequently in KO neurons; clustering experiments at 37°C leave open a possible exocytosis contribution.
  • Evident from the text: colocalization and correlation analyses cannot establish causality or direction of trafficking; no sex-specific analysis is reported despite use of both sexes; replication is modest (n = 3 biological replicates for BS3, n = 15–20 images, ~40 dendrite stretches), and no electrophysiology is performed in this study.

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

Integrity signals

Registry

Crossref · 10.3389/fphar.2025.1568908

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 51 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Rab11 puncta size was significantly increased in SynDIG4 KO neurons.

    “Additionally, we observed that Rab11 puncta size was significantly increased in SynDIG4 KO neurons, whereas the sizes of Rab4 and EEA1 puncta remained unchanged (Figures 4G–I).”
    Quote in the paperSubstantial claim
  • Findingown data

    The percentage of sGluA1 puncta overlapped with PSD95 puncta was decreased in SynDIG4 KO neurons.

    “The percentage of sGluA1 puncta overlapped with PSD95 puncta was decreased in SynDIG4 KO neurons (Figure 5B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Total expression levels of Rab4, Rab11 and EEA1 were comparable between WT and SynDIG4 KO neurons.

    “Meanwhile, the total expression levels of Rab4, Rab11 and EEA1 were comparable between WT and SynDIG4 KO neurons (Supplementary Figures S4D–I).”
    Quote in the paperSubstantial claim
  • Findingown data

    Basal endocytosis of GluA1-containing AMPARs is unchanged in cultured hippocampal neurons from SynDIG4 KO mice compared to WT.

    “We did not observe any change in baseline endocytosis”
    • Also stated in: § SynDIG4 regulates the recycling of GluA1-containing AMPARs · plain
      “After 30 min of internalization, the levels of enGluA1 were comparable between WT and SynDIG4 KO neurons (Figures 2B,C).”
    Quote in the paperSubstantial claim
  • Findingown data

    12.63% of all SynDIG4 signals overlapped with Rab4-Rab11 colocalization sites.

    “Further analysis showed that 59.74% of Rab4-Rab11 colocalization sites contained SynDIG4; however, this represented only 12.63% of all SynDIG4 signals that overlapped with Rab4-Rab11 colocalization sites (data not shown).”
    Quote in the paperNot a substantial claim
  • It may state two separate claims as one. 30
  • Probably not a substantial claim. 15
  • The quote only partly states this claim. 1

  • It may state two separate claims as one.

    Findingown data

    The correlation coefficients for GluA1/Rab4 and GluA2/Rab4 were significantly higher in SynDIG4 KO neurons compared to WT neurons.

    “Notably, the correlation coefficients for GluA1/Rab4 and GluA2/Rab4 were significantly higher in SynDIG4 KO neurons compared to WT neurons (Supplementary Figures S3C, F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The Pearson correlation between GluA1 or GluA2 and endosomal markers peaked at a 0-pixel shift and decreased with increasing pixel shifts, indicating spatial colocalization.

    “The peak Pearson correlation occurred at a 0-pixel shift of the original images, and the correlation values progressively decreased with increasing pixel shifts, indicating spatial colocalization (Supplementary Figures S3A–F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The levels of endocytosed GluA1-containing AMPARs and their localization in early endosomes were comparable between WT and SynDIG4 KO neurons.

    “We found that the levels of endocytosed GluA1-containing AMPARs and their localization in early endosomes were comparable between WT and SynDIG4 KO neurons, indicating that SynDIG4 does not play a role in the endocytosis of GluA1-containing AMPARs under basal conditions.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    While the total GluA1 level at synapses is increased, its surface expression was reduced, implying that intracellular GluA1 may be retained within the synaptic region.

    “These findings indicate that while the total GluA1 level at synapses is increased, its surface expression was reduced, implying that intracellular GluA1 may be retained within the synaptic region.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    SynDIG4 likely regulates the trafficking and distribution of AMPARs rather than their expression.

    “Combined with the current results, these findings indicate that SynDIG4 likely regulates the trafficking and distribution of AMPARs rather than their expression.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In native cryo-EM structures, SynDIG4 association with AMPARs appears to be through the M4 helix of GluA1.

    “In native cryo-EM structures, SynDIG4 association with AMPARs appears to be through the M4 helix of GluA1 (Yu et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yu et al., 2021

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

  • It may state two separate claims as one.

    Study design and conductown data

    BS3 selectively cross-links surface proteins, as no aggregation of β-tubulin was observed after BS3 treatment.

    “After BS3 treatment on one hemisphere of the brain slice, no aggregation of β-tubulin was observed, confirming that BS3 selectively cross-links surface proteins (Figure 1A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Disruption of fusion between Rab4-positive and Rab11-positive endosomes leads to a decrease in the surface expression of AMPARs and an increased colocalization of AMPARs with syntaxin13, a recycling endosome marker.

    “This disruption leads to a decrease in the surface expression of AMPARs and an increased colocalization of AMPARs with syntaxin13, a recycling endosome marker (Chiu et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chiu et al., 2017 source

  • It may state two separate claims as one.

    Interpretationown data

    GluA1 and GluA2 are retained in Rab4-positive endosomes in the absence of SynDIG4, thereby impairing their recycling to the plasma membrane.

    “These findings suggest that GluA1 and GluA2 are retained in Rab4-positive endosomes in the absence of SynDIG4, thereby impairing their recycling to the plasma membrane.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: SynDIG4 knockout does not cause compensatory changes in endosomal trafficking machinery that could account for the observed retention of GluA1 and GluA2 in Rab4-positive endosomes.

  • Probably not a substantial claim.

    Premisecitation

    AMPARs can be recycled to the plasma membrane through different endosomal trafficking pathways.

    “AMPARs can be recycled to the plasma membrane through different endosomal trafficking pathways (Grant and Donaldson, 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grant and Donaldson, 2009 source

  • It may state two separate claims as one.

    Interpretationown data

    SynDIG4 is not specifically enriched in Rab4-positive or Rab11-positive endosomes; rather it is equally distributed across the two compartments and likely plays functional roles at or between Rab4-positive and Rab11-positive endosomes.

    “These findings suggest that SynDIG4 is not specifically enriched in Rab4-positive or Rab11-positive endosomes; rather it is equally distributed across the two compartments and likely plays functional roles at or between Rab4-positive and Rab11-positive endosomes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Rab4 and Rab11 mediate the recycling of endocytosed AMPARs from sorting and recycling endosomes, respectively, during basal conditions.

    “Rab4 and Rab11 mediate the recycling of endocytosed AMPARs from sorting and recycling endosomes, respectively, during basal conditions (Gu et al., 2016; Hausser and Schlett, 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gu et al., 2016

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

    • cites Hausser and Schlett, 2019 source

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

    Study design and conductown data

    Dynasore treatment decreased enGluA1 levels in WT neurons as expected.

    “Dynasore treatment decreased enGluA1 levels in WT neurons as expected (Supplementary Figures S2C, D).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    In SynDIG4 KO neurons, the levels of intracellular AMPARs are increased, impairing the Rab4-Rab11-dependent recycling process.

    “Consequently, the levels of intracellular AMPARs are increased, impairing the Rab4-Rab11-dependent recycling process.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Impaired fusion between Rab4- and Rab11-positive endosomal compartments reduces surface expression of GluA1- and GluA2-containing AMPARs.

    “Impaired fusion between Rab4- and Rab11-positive endosomal compartments has been shown to reduce the surface expression of GluA1-and GluA2-containing AMPARs (Hoogenraad et al., 2010; Chiu et al., 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hoogenraad et al., 2010 source
    • cites Chiu et al., 2017 source

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

    Study design and conductown data

    Some receptors were internalized during the GluA1-N antibody-feeding process.

    “During the GluA1-N antibody-feeding process, some receptors were internalized (Supplementary Figure S2A).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Endocytosis is likely required for the clustering of live-labeled GluA1 and GluA2, but not GluK2, with SynDIG4.

    “Interestingly, our prior study investigating the distribution of SynDIG4 and AMPARs in heterologous cells proposed that endocytosis is likely required for the clustering of live-labeled GluA1 and GluA2, but not GluK2, with SynDIG4 (Plambeck et al., 2022).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Plambeck et al., 2022 source

  • It may state two separate claims as one.

    Interpretationown data

    SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions.

    “Collectively, these results indicate that SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    SynDIG4 slows deactivation kinetics of both GluA1 homomers and GluA1/GluA2 heteromers.

    “Similar to other AMPAR auxiliary factors (Jackson and Nicoll, 2011), SynDIG4 slows deactivation kinetics of both GluA1 homomers and GluA1/GluA2 heteromers.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jackson and Nicoll, 2011 source
    • cites Matt et al., 2018 source

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

    Premisecitation

    SynDIG4 reduces desensitization only of GluA1 homomers and has no significant effect on desensitization of heteromeric GluA1/GluA2.

    “In contrast, SynDIG4 reduces desensitization only of GluA1 homomers and has no significant effect on desensitization of heteromeric GluA1/GluA2 (Matt et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Matt et al., 2018 source

  • It may state two separate claims as one.

    Premiseown data

    SynDIG4 functions as an auxiliary factor of AMPARs and plays a critical role in excitatory synaptic plasticity and hippocampal-dependent learning and memory.

    “The transmembrane protein Synapse Differentiation Induced Gene 4 (SynDIG4) functions as an auxiliary factor of AMPA receptors (AMPARs) and plays a critical role in excitatory synaptic plasticity as well as hippocampal-dependent learning and memory.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Shanks et al., 2012 source
    • cites Troyano-Rodriguez et al., 2019 source
    • cites Matt et al., 2018 source

  • It may state two separate claims as one.

    Interpretationown data

    SynDIG4 plays a critical role in the endosomal trafficking of GluA1-containing AMPARs via Rab4-positive recycling pathways and is essential for the proper distribution of surface AMPARs at synapses.

    “In summary, our findings demonstrate that SynDIG4 plays a critical role in the endosomal trafficking of GluA1-containing AMPARs via Rab4-positive recycling pathways and is essential for the proper distribution of surface AMPARs at synapses.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    SynDIG4 promotes the surface expression of GluA1-containing AMPARs via the Rab4-dependent recycling pathway and regulates the synaptic localization of sGluA1.

    “Overall, our findings suggest that SynDIG4 promotes the surface expression of GluA1-containing AMPARs via the Rab4-dependent recycling pathway and regulates the synaptic localization of sGluA1.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    SynDIG4 is important for the recycling but not for the endocytosis process of GluA1-containing AMPARs at the plasma membrane.

    “indicating that SynDIG4 is important for the recycling but not for the endocytosis process of GluA1-containing AMPARs at the plasma membrane.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Rab11 is involved in the continuous recycling of endocytosed GluA1-containing AMPARs to the postsynaptic membrane via an EEA1-Rab4-Rab11 endosomal pathway.

    “Rab11 is involved in the continuous recycling of endocytosed GluA1-containing AMPARs to the postsynaptic membrane via an EEA1-Rab4-Rab11 endosomal pathway (Esteves da Silva et al., 2015; Lisé et al., 2006; Wang et al., 2008; Park et al., 2004); however, AMPARs can also return to the surface directly from Rab4-positive compartments as was shown for GluA2 (Gu et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Esteves da Silva et al., 2015 source
    • cites Lisé et al., 2006 source
    • cites Wang et al., 2008 source

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

    Premisecitation

    In Xenopus oocytes, SynDIG4 modulates AMPAR gating properties in a subunit-dependent manner.

    “In Xenopus oocytes, SynDIG4 was shown to modulate AMPAR gating properties in a subunit-dependent manner (Matt et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Matt et al., 2018 source

  • It may state two separate claims as one.

    Interpretationreasoning

    SynDIG4 plays a critical role in both the surface expression and synaptic localization of AMPARs.

    “These findings suggest that SynDIG4 plays a critical role in both the surface expression and synaptic localization of AMPARs.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    NMDAR-dependent LTD and single tetanus-induced LTP require calcium-permeable AMPARs, which are mostly GluA1 homomers.

    “Intriguingly, both NMDAR-dependent LTD (Troyano-Rodriguez et al., 2019) and single tetanus-induced LTP (Matt et al., 2018), which require calcium-permeable AMPARs (Sanderson et al., 2016), which are mostly GluA1 homomers, are impaired in SynDIG4 deficient neurons while baseline synaptic transmission is intact.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sanderson et al., 2016 source

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

    Premisecitation

    Recycling of AMPARs through Rab4-Rab11-associated recycling endosomes and directly from Rab4-positive endosomes are both important for the supply for synaptic AMPARs.

    “Interestingly, recycling of AMPARs through Rab4-Rab11-associated recycling endosomes and directly from Rab4-positive endosomes are both important for the supply for synaptic AMPARs (Gu et al., 2016; Hausser and Schlett, 2019).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gu et al., 2016

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

    • cites Hausser and Schlett, 2019 source

  • It may state two separate claims as one.

    Premisecitation

    Both NMDAR-dependent LTD and single tetanus-induced LTP are impaired in SynDIG4 deficient neurons while baseline synaptic transmission is intact.

    “Intriguingly, both NMDAR-dependent LTD (Troyano-Rodriguez et al., 2019) and single tetanus-induced LTP (Matt et al., 2018), which require calcium-permeable AMPARs (Sanderson et al., 2016), which are mostly GluA1 homomers, are impaired in SynDIG4 deficient neurons while baseline synaptic transmission is intact.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Troyano-Rodriguez et al., 2019 source
    • cites Matt et al., 2018 source

  • It may state two separate claims as one.

    Premisecitation

    SynDIG4 overlaps primarily with extrasynaptic AMPARs and localizes to early and recycling endosomes.

    “SynDIG4 overlaps primarily with extrasynaptic AMPARs (Kirk et al., 2016) and localizes to early and recycling endosomes (Martin et al., 2021).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kirk et al., 2016 source
    • cites Martin et al., 2021 source

  • It may state two separate claims as one.

    Study design and conductown data

    Fab antibodies block surface GluA1 and GluA2 signals, as sGluA1 and sGluA2 signals cannot be detected after adding Fab.

    “As a control, sGluA1 and sGluA2 signals cannot be detected after adding Fab (Supplementary Figure S1E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one. The quote only partly states this claim.

    Study design and conductown data

    The staining procedure exhibits high specificity and adequate efficiency, as >90% of enGluA1 and reGluA1 colocalized with tGluA1 in both WT and SynDIG4 KO neurons.

    “The percentages of enGluA1 and reGluA1 colocalizing with tGluA1 were greater than 90% in both WT and SynDIG4 KO neurons (Figures 2C,F).”
    • Also stated in: § SynDIG4 regulates the recycling of GluA1-containing AMPARs · boosted
      “These findings confirm that, despite the presence of some background noise, the staining procedure exhibits high specificity and adequate efficiency.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Impaired fusion between Rab4-positive and Rab11-positive endosomes leads to increased overlap between Rab4 and Rab11 compartments, thereby disrupting AMPAR trafficking.

    “Previous work proposed a model that impaired fusion between Rab4-positive and Rab11-positive endosomes leads to increased overlap between Rab4 and Rab11 compartments, thereby disrupting AMPAR trafficking (Hoogenraad et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hoogenraad et al., 2010 source

  • It may state two separate claims as one.

    Premisecitation

    SynDIG4 KO neurons display deficits in LTD and single-tetanus LTP, both of which require GluA1.

    “SynDIG4 KO neurons display deficits in LTD (Troyano-Rodriguez et al., 2019) and single-tetanus LTP (Matt et al., 2018), both of which require GluA1.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Troyano-Rodriguez et al., 2019 source
    • cites Matt et al., 2018 source

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

    Premisecitation

    Downregulation of SynDIG4 has been found in patients with Alzheimer's disease.

    “SynDIG4 KO mice also display deficits in hippocampal-dependent learning and memory (Matt et al., 2018), and downregulation of SynDIG4 has been found in patients with Alzheimer’s disease (Li et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li et al., 2021

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

  • It may state two separate claims as one.

    Premisecitation

    Mice lacking SynDIG4 are impaired in single tetanus-induced LTP and NMDAR-dependent LTD.

    “Mice lacking SynDIG4 have reduced surface expression of GluA1 and GluA2 and are impaired in single tetanus-induced long-term potentiation and NMDA receptor (NMDAR)-dependent long-term depression.”
    • Also stated in: § Introduction · plain
      “Furthermore, NMDA receptor (NMDAR)-dependent long-term depression (LTD) (Troyano-Rodriguez et al., 2019) and single tetanus-induced long-term potentiation (LTP) (Matt et al., 2018) are impaired in SynDIG4 KO neurons while baseline synaptic transmission is intact.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Troyano-Rodriguez et al., 2019 source
    • cites Matt et al., 2018 source

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

    Premisecitation

    AMPARs can return to the surface directly from Rab4-positive compartments, as shown for GluA2.

    “Rab11 is involved in the continuous recycling of endocytosed GluA1-containing AMPARs to the postsynaptic membrane via an EEA1-Rab4-Rab11 endosomal pathway (Esteves da Silva et al., 2015; Lisé et al., 2006; Wang et al., 2008; Park et al., 2004); however, AMPARs can also return to the surface directly from Rab4-positive compartments as was shown for GluA2 (Gu et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gu et al., 2016

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

  • It may state two separate claims as one.

    Interpretationown data

    Recycling of GluA1-containing AMPARs was impaired in SynDIG4 KO neurons likely due to trafficking defects between Rab4-positive and Rab11-positive recycling endosomes, thereby reducing the levels of sGluA1 at synaptic sites.

    “In contrast, recycling of GluA1-containing AMPARs was impaired in SynDIG4 KO neurons likely due to trafficking defects between Rab4-positive and Rab11-positive recycling endosomes, thereby reducing the levels of sGluA1 at synaptic sites (Figure 6).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Some SynDIG4 colocalizes with the early endosomal marker EEA1 and with the transferrin receptor which is recycled between endosomes and the plasma membrane.

    “Previous studies have shown that some SynDIG4 colocalizes with the early endosomal marker EEA1 and with the transferrin receptor which is recycled between endosomes and the plasma membrane (Martin et al., 2021), suggesting that SynDIG4 is involved in recycling of AMPARs via the endosomal pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Martin et al., 2021 source
40 of 40

  • The paper relies on this without support.

    SynDIG4 knockout does not cause compensatory changes in endosomal trafficking machinery that could account for the observed retention of GluA1 and GluA2 in Rab4-positive endosomes.

    “These findings suggest that GluA1 and GluA2 are retained in Rab4-positive endosomes in the absence of SynDIG4, thereby impairing their recycling to the plasma membrane.”

  • The paper relies on this without support.

    The colocalization of Rab4 and Rab11 signals reflects functional trafficking between these compartments rather than random spatial proximity.

    “Interestingly, the overlap between Rab4 signals and Rab11 signals was increased in SynDIG4 KO neurons, suggesting that endosomal trafficking between Rab4-positive and Rab11-positive endosomes is disrupted in SynDIG4 KO neurons (Figures 4B, E; Supplementary Figure S4B).”
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Metadata

Authors
He, C.-W., & Díaz, E.
Affiliations
University of California, Davis (US)
ORCID
He, Chun-Wei
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2025-05-21
Volume
16
Pages
1568908-1568908
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2025.1568908
PMC
PMC12133753
OpenAlex
W4410571395
Cited by
3
References
48
Citations by year
2026: 2 · 2025: 1
FWCI
0.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • University of California, Davis
  • National Institute of Mental Health (R01MH119347)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
AMPA receptors, GluR1, GluA2, receptor recycling, endosomal trafficking, Rab4, Rab11, recycling endosomes, endocytosis, synaptic plasticity, hippocampal neurons, excitatory synapses, learning and memory

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 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

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

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

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