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A trans-synaptic nanocolumn aligns neurotransmitter release to receptors
Open accessAbstract
Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular ‘nanocolumn’. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor–scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency.
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TL;DR
Using super-resolution localization microscopy and a new pHluorin-based method (pHuse) to map single-vesicle fusion, this paper shows that presynaptic RIM1/2 nanoclusters align transsynaptically with postsynaptic PSD-95/receptor nanoclusters in a “nanocolumn.” This alignment directs action-potential-evoked release to high-RIM regions opposite receptor-rich postsynaptic sites and is reorganized during NMDAR-dependent plasticity.
Key findings
- Presynaptic active-zone proteins are nonuniformly organized into nanoclusters: RIM1/2 nanoclusters averaged ~80 nm in diameter, similar to PSD-95 and AMPA receptor nanoclusters; Munc13 had more nanoclusters per synapse than PSD-95, while Bassoon had fewer and was closer to uniform.
- pHuse mapping showed single action potentials evoked release with Pr = 0.11 ± 0.01 per bouton, and ~72–82% of evoked events arose from single-vesicle fusion. Evoked fusion site areas were median 48% smaller and occupied a median 39% smaller proportion of the bouton than spontaneous fusion, and RIM1 density was significantly higher near pHuse sites than chance.
- RIM1/2 was enriched within 60 nm of PSD-95 nanocluster centers, decaying e-fold per 43.2 ± 12.1 nm; 44.4 ± 3.0% of PSD-95 nanoclusters were enriched, opposing RIM1/2 densities 2.0 ± 0.1 times the average synaptic RIM1/2 density. GluA2 was similarly enriched relative to RIM1/2 nanoclusters, decaying e-fold per 66.9 ± 15.4 nm.
- A model constrained by measured RIM1/2 and GluA2/3 distributions estimated that transsynaptic alignment gained 21.8 ± 0.5% in synaptic strength versus a uniform distribution. Chemical LTP increased PSD-95 nanocluster density and RIM1/2 enrichment (blocked by APV), while acute NMDA treatment first disrupted PSD-95 nanostructure and later increased RIM1/2 enrichment and the size of aligned RIM1/2 nanoclusters.
Methods
- Dissociated hippocampal neurons from E18 rats were imaged at 14–21 DIV, with additional acute hippocampal slices from 5–7-week-old male rats; proteins were immunolabeled and imaged with 3D-STORM, PALM, and sequential two-/three-color STORM.
- Vesicle fusion was mapped with vGlut1-pHluorin-mCherry plus Synapsin1a-CFP using pHuse, with single action-potential field stimulation and spontaneous release in TTX; RIM1-mEos3.1 PALM was performed sequentially on the same boutons. Analyses included autocorrelation and pair cross-correlation functions, Voronoï/SR-Tesseler density, nanocluster detection, protein enrichment profiles, and randomization simulations.
- Plasticity used chemical LTP via APV withdrawal plus glycine and chemical LTD via NMDA application. Synaptic strength was modeled deterministically using measured RIM1/2 and GluA2/3 coordinates and a previously derived AMPAR opening-probability function, Po(r) = 0.42e−r/88nm.
Limitations
- The paper states that nanocluster detection criteria were conservative and may have prevented detection of small or weakly enriched nanoclusters; it also states that overcounting cannot be completely excluded, so some detected nanoclusters are potentially artificial, though the same standard was applied across datasets and randomization controls should not produce false positives for transsynaptic alignment.
- The paper notes that pHuse localization precision was in practice limited by vesicle diameter, and the synaptic model relies on assumptions including a 20 nm cleft distance and a fitted release-likelihood function constrained to a 40% release area.
- Evident from the text: most structural and pHuse experiments used cultured hippocampal neurons, with acute slices used mainly to confirm nanocluster alignment; the model also depends on prior stochastic estimates of receptor activation rather than direct measurement of release-receptor coupling.
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Claims the paper makes
96 Own result · 23 Own interpretation · 15 Own method · 11 Partly supported · 6 No full text of the sources · 4 No basis given · 3 Supported · 2 Supported so far · 2 Mixed support · 2 Couldn’t confirm · 1 Sources not found · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“The average estimated diameter of ~80 nm for RIM1/2 NCs was very close to the reported size of PSD-95 and AMPA receptor (AMPAR) NCs4–6.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Partly supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) sourceExperimental — accuracy not yet measured
The Results section, “Scaffold molecules are organized in subsynaptic clusters” (page unavailable), reports a PSD-95 subcluster diameter of 83 ± 4 nm, close to the citing sentence’s ~80 nm. The Results section, “Subsynaptic scaffolding domains concentrate synaptic AMPARs” (page unavailable), reports AMPAR enrichment within those domains but does not give a separate AMPAR nanocluster diameter. This source therefore supports the PSD-95 size comparison, but not the stated AMPAR nanocluster size. (LLM, conf=0.84)
- Partly supportedcites [5] Nair, D. et al. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J. Neurosci. 33, 13204–13224 (2013) sourceExperimental — accuracy not yet measured
The ‘Subsynaptic AMPAR clusters’ section reports AMPAR nanodomain axes near 80 nm, supporting that comparison. But ‘Nanoscale co-organization of PSD95 and AMPARs’ (Fig. 7E) reports PSD95 subdomain axes of 158.2 and 102.2 nm and explicitly describes the AMPAR nanodomains as smaller. The copy does not support treating both reported sizes as very close to 80 nm. (LLM, conf=0.85)
- Disputedcites [6] Fukata, Y. et al. Local palmitoylation cycles define activity-regulated postsynaptic subdomains. J. Cell Biol. 202, 145–161 (2013) sourceExperimental — accuracy not yet measured
The Results section (page unavailable) reports a mean diameter of about 200 nm for palmitoylated PSD-95 nanodomains, not a size very close to the citing sentence’s ~80 nm. It reports that AMPAR clusters associate with those nanodomains but gives no AMPAR-cluster diameter. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These presynaptic RIM nanoclusters closely aligned with concentrated postsynaptic receptors and scaffolding proteins4–6, suggesting a transsynaptic molecular “nanocolumn.””
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Partly supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) sourceExperimental — accuracy not yet measured
The Results section reports that AMPA receptors are enriched in postsynaptic PSD-95 scaffold clusters. The Discussion proposes pre–post alignment as a possibility but also says these clusters may concentrate receptors toward the synapse’s center rather than specifically align them with release sites. It does not establish close alignment with presynaptic RIM nanoclusters. (LLM, conf=0.88)
- Partly supportedcites [5] Nair, D. et al. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J. Neurosci. 33, 13204–13224 (2013) sourceExperimental — accuracy not yet measured
The Abstract reports concentrated postsynaptic AMPA-receptor nanodomains that are often, but not always, colocalized with PSD95 scaffold clusters. The Discussion only proposes a possible correlation with presynaptic release sites; it does not establish that presynaptic RIM nanoclusters closely align with those postsynaptic clusters. No page numbers are available in our copy. (LLM, conf=0.88)
- Partly supportedcites [6] Fukata, Y. et al. Local palmitoylation cycles define activity-regulated postsynaptic subdomains. J. Cell Biol. 202, 145–161 (2013) sourceExperimental — accuracy not yet measured
The Results section on subsynaptic nanodomains (Fig. 4F–H; page unavailable) shows postsynaptic PSD-95 nanodomains associated with AMPA receptors and apposed to presynaptic vGlut1 labeling. It does not identify presynaptic RIM nanoclusters or show that those clusters closely align with the postsynaptic proteins. (LLM, conf=0.86)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“as the PSD-95 NCs concentrate higher density of receptors7.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Could not verifycites [7] Südhof, T. C. The presynaptic active zone. Neuron 75, 11–25 (2012) sourceExperimental — accuracy not yet measured
The passages from “Membrane Proteins of Active Zones” discuss receptors concentrated in presynaptic active zones, not receptors concentrated by PSD-95 nanoclusters. Searches for “PSD-95 nanoclusters” and “PSD-95 postsynaptic density receptors clustering” found no passage in our copy addressing the claim. (LLM, conf=0.76)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The alignment of pre and postsynaptic nanoscale subdomains4–6 suggests that even small synapses may be composed of dynamic functional modules28,29.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) source
The Discussion describes nanoscale postsynaptic scaffold domains whose reorganization can affect transmission, even without a change in receptor number. The Results report that these domains change over time in living synapses. This supports the cited suggestion of dynamic functional modules; the sentence cites other sources for pre- and postsynaptic alignment. (LLM, conf=0.88)
- Partly supportedcites [5] Nair, D. et al. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J. Neurosci. 33, 13204–13224 (2013) sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) describes dynamic AMPAR nanodomains that may act as functional units activated by single-vesicle release, supporting the proposed module concept. The cited paper does not specifically establish that this organization occurs in small synapses; the sentence’s alignment claim is attached to other citations. (LLM, conf=0.78)
- Supportedcites [6] Fukata, Y. et al. Local palmitoylation cycles define activity-regulated postsynaptic subdomains. J. Cell Biol. 202, 145–161 (2013) source
The Results section ('Subsynaptic nanodomains of palmitoylated PSD-95 as building blocks of the PSD'; page unavailable) describes one to four nanodomains per spine and associates individual nanodomains with AMPA receptors. The Discussion (page unavailable) models these domains as building blocks that can be created through local palmitoylation, while the Results report activity-dependent remodeling. This supports the hedged suggestion of dynamic functional modules; the preceding claim about pre- and postsynaptic alignment is attached to other citations. (LLM, conf=0.86)
- Supportedcites [28] Tarr, T. B., Dittrich, M. & Meriney, S. D. Are unreliable release mechanisms conserved from NMJ to CNS? Trends Neurosci. 36, 14–22 (2013) source
The section ‘The unreliable single vesicle release site as a basic building block of synapses’ proposes functional release sites as units from which synapses are assembled. The Conclusions state that smaller synapses have a few such sites and describe how their calcium-channel coupling can change during maturation. This supports the hedged claim about small synapses comprising dynamic functional modules; the alignment claim is attached to other citations. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [29] Lisman, J. & Raghavachari, S. A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses. Sci. STKE 2006, re11 (2006) source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Nevertheless, sensitivity of PSD-95 NC size to latrunculin4 further suggests that the spine cytoskeleton is engaged at the “base” of the column.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) source
The Discussion reports that acute actin depolymerization with latrunculin A reduced the area of PSD-95 clusters. It also describes actin filaments contacting the PSD at its interior face, supporting the cited observation and the hedged inference about cytoskeletal engagement. The “base of the column” is the citing authors’ framing. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For the synapse as a whole, the impact of presynaptic nanoscale organization and confined vesicle sites (Fig. 1, 2) will depend strongly on whether these RIM NCs align with postsynaptic receptor NCs4.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Partly supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) sourceExperimental — accuracy not yet measured
The Results section (‘Clustered distribution shapes postsynaptic responses’; page not provided) reports simulated currents nearly twice as large when vesicles released glutamate over AMPA-receptor clusters rather than off-cluster. The Discussion identifies pre–post alignment as a way to maximize transmission, but does not establish that this effect depends on alignment of RIM nanoclusters specifically; it also reports an advantage for clustered receptors even with randomly distributed release sites. (LLM, conf=0.85)
boostedconditional- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“we compared them with spontaneous release in TTX (Fig. 2a–c), which most likely arises from single vesicle fusion13.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Supportedcites [13] Leitz, J. & Kavalali, E. T. Fast retrieval and autonomous regulation of single spontaneously recycling synaptic vesicles . eLife 3, e03658 (2014) source
In the Results section, the paper identifies spontaneous fusion events recorded in TTX. Its analysis estimates that 17% of events at 2 mM extracellular Ca²⁺ were multivesicular, supporting the claim that spontaneous release under those conditions most likely arises from single-vesicle fusion. The multivesicular fraction increased at higher Ca²⁺ concentrations. (LLM, conf=0.92)
hedged- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“evoked Pr was significantly positively correlated with Syn1a area, as reported previously50”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
What the sources say
- Could not verifycites [50] Ermolyuk, Y. S. et al. Differential triggering of spontaneous glutamate release by P/Q-, N- and R-type Ca2+ channels. Nat. Neurosci. 16, 1754–1763 (2013) sourceExperimental — accuracy not yet measured
The Results section on modeling action potential-evoked release reports vesicular fusion probabilities for different channel-distribution models, but not a correlation with Syn1a area. Searches for “Syn1a,” synapsin area, and evoked release probability versus bouton area found no passage reporting the claimed correlation. Page numbers were unavailable in our copy. (LLM, conf=0.72)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“The extent of ga(r) over 1, i.e. r0 for ga(r0) =1, is related to the pattern size of the internal heterogeneity (Extended Data Figure 2b–c)39.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Autocorrelation function (ACF) analysis
What the sources say
- Supportedcites [39] Veatch, S. L. et al. Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting. PLoS One 7, e31457 (2012) source
In Results and Discussion, under “Pair correlation functions quantify heterogeneity,” the paper says the shape and range of a correlation function reveal the structure underlying heterogeneity. Its Figure 3 description gives a model for circular domains in which g(r) reaches 1 at the average circle radius, directly linking that crossing distance to pattern size. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“we induced long-term potentiation via APV withdrawal and glycine stimulation19”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Partly supportedcites [19] Araki, Y., Zeng, M., Zhang, M. & Huganir, R. L. Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron 85, 173–189 (2015) sourceExperimental — accuracy not yet measured
The Experimental Procedures section (page unavailable) describes inducing LTP by perfusing hippocampal neurons with glycine-containing, magnesium-free solution. The paper lists APV as a reagent and reports that APV blocks chemLTP-induced SynGAP dispersion, but our copy does not describe APV withdrawal as part of the induction method. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
- It may state two separate claims as one. 39
- Probably not a substantial claim. 42
- The quote only partly states this claim. 3
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“However, observations in small CNS synapses of both clustered24,25 and random distribution of Ca2+ channels26, and emerging evidence for channel mobility as an equalizer of Pr for vesicles independent of channel positioning27 suggest that their precise distribution may not be the sole determinant of the AZ release likelihood landscape.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Disputedcites [24] Holderith, N. et al. Release probability of hippocampal glutamatergic terminals scales with the size of the active zone. Nat. Neurosci. 15, 988–997 (2012) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
- Disputedcites [25] Nakamura, Y. et al. Nanoscale distribution of presynaptic Ca2+ channels and its impact on vesicular release during development. Neuron 85, 145–158 (2015) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
- Supportedcites [26] Scimemi, A. & Diamond, J. S. The number and organization of Ca2+ channels in the active zone shapes neurotransmitter release from Schaffer collateral synapses. J. Neurosci. 32, 18157–18176 (2012) source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [27] Schneider, R. et al. Mobility of calcium channels in the presynaptic membrane. Neuron 86, 672–679 (2015) source
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“We next tested an acute 5-minute activation of NMDARs, known to induce a sustained depression of synaptic strength20,21.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Not checked — no full text of the sourcecites [20] Lee, H.-K., Kameyama, K., Huganir, R. L. & Bear, M. F. NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus. Neuron 21, 1151–1162 (1998) source
- Supportedcites [21] Sanderson, J. L. et al. AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors. J. Neurosci. 32, 15036–15052 (2012) source
The Results section (page unavailable) says brief NMDA application produces chemical long-term depression. It also reports that a 5-minute NMDA treatment removed GluA1 AMPA receptors from synapses in wild-type neurons, with the reduction persisting for at least 30 minutes. This supports the paraphrase, although the 5-minute experiment measured receptor localization rather than synaptic strength directly. (LLM, conf=0.87)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“given that the probability of AMPAR activation declines with distance from glutamate release sites has previously been deduced3,16”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Supportedcites [3] Franks, K. M., Stevens, C. F. & Sejnowski, T. J. Independent sources of quantal variability at single glutamatergic synapses. J. Neurosci. 23, 3186–3195 (2003) source
In “Dependence on release location,” the paper reports that the open probability of an individual AMPA receptor decreased as its distance from the glutamate release site increased. Figure 7C in “Implications of RLD” likewise describes a decreasing average probability of receptor activation with increasing radial distance from release. (LLM, conf=0.95)
- Not checked — no full text of the sourcecites [16] Raghavachari, S. & Lisman, J. E. Properties of quantal transmission at CA1 synapses. J. Neurophysiol. 92, 2456–2467 (2004) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The distribution of RIM1-mEos3 was nonuniform and contained NCs with an average diameter of 80.95 ± 5.34 nm and 78.93 ± 5.85 nm using either an adapted SR-Tesseler analysis15 or nearest neighbor distance analysis4, respectively (Extended Data Fig. 6f), consistent with our 3D-STORM results (Fig. 1).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Not checked — no full text of the sourcecites [15] Levet, F. et al. SR-Tesseler: a method to segment and quantify localization-based super-resolution microscopy data. Nat. Methods 12, 1065–1071 (2015) source
- Partly supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) sourceExperimental — accuracy not yet measured
In Results (‘Scaffold molecules are organized in subsynaptic clusters’; page unavailable), the source reports postsynaptic scaffold clusters with an 83 ± 4 nm diameter, broadly consistent with the cited sentence’s nanoscale-cluster comparison. It does not report RIM1-mEos3 measurements or either stated diameter, and its described analyses count neighbors within a radius and use pair-correlation and Monte Carlo methods rather than explicitly identifying a nearest-neighbor distance analysis. (LLM, conf=0.82)
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“To test this, we induced long-term potentiation via APV withdrawal and glycine stimulation19 which resulted in an increase in PSD-95 localization density within NCs, the percentage of PSD-95 NCs enriched with RIM1/2, and the enrichment index of PSD-95 NCs (Fig. 4a–c, Extended Data Fig. 10m).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Partly supportedcites [19] Araki, Y., Zeng, M., Zhang, M. & Huganir, R. L. Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron 85, 173–189 (2015) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“GCaMP6f was used to detect postsynaptic miniature spontaneous Ca2+ transients (mSCaTs) that arose in dendritic spines following NMDA receptor activation by spontaneous release46.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Ca2+ imaging and analysis
What the sources say
- Partly supportedcites [46] Murthy, V. N., Sejnowski, T. J. & Stevens, C. F. Dynamics of dendritic calcium transients evoked by quantal release at excitatory hippocampal synapses . Proc. Natl Acad. Sci. USA 97, 901–906 (2000) sourceExperimental — accuracy not yet measured
The Abstract reports fluorescence detection of NMDA receptor-mediated miniature calcium transients caused by spontaneous vesicle release in dendrites. But Methods > Calcium Imaging specifies fluo-3, not GCaMP6f, and the Discussion says the authors generally could not resolve spines; it does not establish that the observed transients arose in spines. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
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In the paper
“TetraSpeck beads (100 nm; Invitrogen) deposited on a coverslip were localized to correct alignment between the two channels as described4. The average deviation of the bead localizations after correction was between 10 and 15 nm.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > 3D STORM Imaging
What the sources say
- Partly supportedcites [4] MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013) sourceExperimental — accuracy not yet measured
The Experimental Procedures (page unavailable) say that images from two channels were acquired simultaneously, drift-corrected, and aligned. Our copy does not say that TetraSpeck beads were used for alignment or report a 10–15 nm average deviation after correction; the Results’ <15 nm figure concerns molecule-localization precision, not bead alignment. (LLM, conf=0.84)
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In the paper
“Syn1a-CFP puncta area calculated as a measure of bouton area, which correlated with pHuse area, as expected42.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > pHuse localization and analysis
What the sources say
- Partly supportedcites [42] Harris, K. M. & Stevens, J. K. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J. Neurosci. 9, 2982–2997 (1989) sourceExperimental — accuracy not yet measured
The Serial electron microscopy section reports that postsynaptic density area was proportional to presynaptic axonal varicosity volume, supporting a general relationship between bouton size and synaptic size. It does not report Syn1a-CFP puncta, pHuse area, or a correlation between those two fluorescence measurements. (LLM, conf=0.82)
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In the paper
“Different from the ACF, overcounting has no effect on the PCF39.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > 3D Pair cross-correlation function (PCF) analysis
What the sources say
- Partly supportedcites [39] Veatch, S. L. et al. Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting. PLoS One 7, e31457 (2012) sourceExperimental — accuracy not yet measured
In Materials and Methods (“Modifications for measured cross-correlation functions”; page unavailable), the paper says pair cross-correlation functions have no over-counting artifact, unlike pair auto-correlation functions. It limits this result to labeling schemes in which two distinguishable probes cannot label the same molecule; the unqualified claim omits that condition. (LLM, conf=0.82)
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In the paper
“we found that action potential evoked fusion was guided by this protein gradient and occurred preferentially in confined areas with higher local density of RIM within the active zones.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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“which was also sensitive to extracellular Ca2+ (Extended Data Fig. 4b–d), as expected.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“An example synapse, presented in Fig. 3a (suppl. Video 1), shows three RIM1/2 NCs and three PSD-95 NCs that appear well-aligned and one pair not aligned.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“In fact, evoked fusion site areas were significantly smaller (median smaller by 48%) and occurred over a significantly smaller proportion of the bouton (median smaller by 39%) than spontaneous fusion (Fig. 2g, Extended Data Fig. 5c–d, h–j).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“In comparison to RIM1/2, the enrichment of Munc13 with respect to PSD-95 NCs was considerably weaker, and Bassoon intermediate (Fig. 3d, g, Extended Data Fig. 7c–e, Suppl. Table 2).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“Fusion site areas for spontaneous and evoked vesicle fusion tightly correlated with bouton areas measured by Syn1a (Fig. 2f), as expected.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“However, the slopes of the correlations differed, even though the bouton sizes were similar between groups (Extended Data Fig. 5b).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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“Compared to PSD-95 as the common control in pairwise two-color experiments, there were similar numbers of RIM1/2, more Munc13, and fewer Bassoon NCs per synapse (Fig. 1h).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“These effects were long-lasting, and during the subsequent 25 minutes, most parameters underwent only partial recovery.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“Remarkably, while RIM1/2 NCs altogether remained constant in number and enriched percentage, there was in fact an increase in the size of those RIM1/2 NCs that were enriched with PSD-95, whereas the other non-enriched RIM1/2 NCs remained constant (Fig. 4i).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“Notably, no changes in RIM1/2 were observed, consistent with LTP as a primarily postsynaptic phenomenon.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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“Together, both the PCFs and protein enrichment analyses revealed significant trans-synaptic alignment between RIM1/2 and PSD-95 distributions, largely stemming from the correlated positions of their respective NCs.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
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In the paper
“which showed that release events preferentially occurred in regions with normalized RIM local density greater than 1.5, and these events occurred over 20–60% of the AZ area”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Synaptic modeling
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In the paper
“We calculated the higher estimate (82%) by calculating the percent of evoked fusion events with photon counts within two standard deviations of the mean spontaneous fusion event photon count.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Photon count distributions analysis
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- Rests on an assumption: The number of photons detected in a pHuse event is proportional to the number of vesicles released.
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In the paper
“Comparison of NC number, fraction of localization in NC, and NC volume across different developmental stages shows no significant difference, though the young DIV9 culture shows a trend toward increased NC numbers”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“This alpha shape algorithm gave a synaptic cluster volume of 81 ± 3 % of the convex hull volume (n = 156 synapses).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Analysis of synaptic clusters
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In the paper
“Neurons coexpressing RIM1-mVenus (a generous gift from Pascal Kaesar) and Syn1a-CFP colocalize to the same boutons.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“The fraction of enriched NCs is significantly above chance level, and is also dependent on the relative position of the two sets of NCs.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“NCs detected in both channels displayed no difference in number, volume, or the fraction of NCs enriched with localizations from the other channel.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Normalized pHuse area was not significantly different at different thresholds for Syn1a within modes of release but still significantly different between modes of release (n = 51/10).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Normalized pHuse area as a function of cell age shows no significant correlation (evoked R = 0.03, n.s., spont R = 0.004, n.s.)”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Paired autocorrelation function of synaptic clusters with and without multiple-frame molecules. p = 0.77, n = 25 synapses for RIM1/2; p = 0.58, n = 25 synapses for PSD-95, two-way ANOVA with repeated measures.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Immunofluorescence intensity of transfected cells normalized to nearby untransfected cells show 3.74 ± 0.11-fold overexpression of RIM and 1.24 ± 0.03-fold increase in Bassoon (n = 262 synapses/7 cells).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“An additional criterion to exclude evoked pHuse localizations with photon counts > mean + 2SD of spontaneous photon count distribution was used in Extended Data Fig. 5d and showed no significant difference compared to the distribution lacking this criterion.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > pHuse localization and analysis
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In the paper
“There were, on average, 2.02 ± 0.08 and 1.32 ± 0.21 NCs with a volume of (3.6 ± 0.2) and (4.2 ± 0.7) × 105 nm3 for RIM1/2 and PSD-95, respectively.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Both proteins showed significant enrichment in PSD-95 NCs, *p<0.05, paired t-tests.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“The tracking removed 13 ± 8% and 17 ± 9% of the localizations for RIM1/2 and PSD-95, respectively, but had no significant effects on autocorrelation function results, NC numbers, or NC volumes.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Both numbers of events and mode of release are significant factors for pHuse area, but they do not have a significant interaction nevoked = 155/38, nspont = 109/29.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Cumulative distributions of normalized fusion areas for 1 AP evoked fusion excluding events with photon counts > mean + 2SD of spontaneous events (n = 91/27) compared to all evoked events (n = 104/28, K–S test, D = 0.05, n.s.) and spontaneous events (n = 77/22, K–S test, D = 0.25*)”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“the calculated synaptic response was independent of pixilation level for sampling size from 1 to 20 nm, data not shown”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Synaptic modeling
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In the paper
“Comparison of spontaneous frequency measured presynaptically using vGpH (n = 77/22) and postsynaptically using GCaMP6f 45(n = 61/5), t = 1.02, n.s.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
plainn = 77- Asserted: passes — The authors put it forward as true.
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In the paper
“Nanoclusters identified by both methods were similar in size (Extended Data Fig. 6).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > PALM-pHuse
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In the paper
“both spontaneous event frequency and evoked Pr significantly positively correlated with pHuse area (f, linear fit, evoked R = 0.64***, spontaneous R = 0.60***)”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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In the paper
“Except PSD NC number which was significantly less than that in cultures (p = 0.03), all other parameters were similar (Wilcoxon signed-rank test).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
plainn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“1AP evoked release is [Ca2+] dependent and mainly univesicular48”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
What the sources say
- Not checked — no full text of the sourcecites [48] Kavalali, E. T. et al. Spontaneous neurotransmission: an independent pathway for neuronal signaling? Physiology (Bethesda) 26, 45–53 (2011) source
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In the paper
“33% and 67% thresholds were also compared and showed no significant difference on the effect of mode of release, shown in Extended Data Fig. 5i”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > pHuse localization and analysis
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In the paper
“Similar detection thresholds were set for spontaneous (75 ± 15) and evoked (78 ± 14, t = 0.88, p = 0.40) release, at ~3–4 times above background noise, on an individual imaging field basis.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > pHuse localization and analysis
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Normalized pHuse area was not significantly different at RT (nevoked = 51/10, nspont = 32/7) vs physiological temperature (nevoked = 35/9, nspont = 34/4) within modes of release but still significantly different between modes of release.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
plainn = 51- Asserted: passes — The authors put it forward as true.
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In the paper
“Average bouton areas across groups, t = 0.87, n.s.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LTP stimulation induced changes in NC volumes (l), localization density within NCs (m) and NC numbers (n). *p<0.05, ANOVA on ranks with pairwise comparison to control group (Dunn’s method).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Extended Data
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It may state two separate claims as one.
In the paper
“The compartmentalized AZ architecture is reminiscent of protein organization in Drosophila neuromuscular junction23 and vertebrate ribbon synapses, where vesicles and priming proteins are arrayed around tight clusters of Ca2+ channels.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Not checked — no full text of the sourcecites [23] Liu, K. S. et al. RIM-binding protein, a central part of the active zone, is essential for neurotransmitter release. Science 334, 1565–1569 (2011) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the gradients of protein density we observed suggest a nanocolumn model, in which AZ regions with the highest likelihood of release are aligned to the densest receptor areas, optimizing the potency of neurotransmission (Suppl. Video 2).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This predicts that pHuse events would be associated with higher local RIM1 density and conversely that high local density of RIM1 increases the probability of nearby fusion.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This and other experiments suggest that the measured nonuniformity was not likely due to over-counting molecules or to potential artifacts of primary-secondary antibody labeling (Extended Data Fig. 3).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This provides a simple organizational principle that may hold for many small, CNS synapses, and will have the largest influence at synapses that typically release only one vesicle following an AP.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The nanocolumn architecture observed in cultured hippocampal neurons and acute hippocampal slices is representative of small CNS synapses generally.
In the paper
“For comparison, long-term depression induces a very similar magnitude decrease in synaptic strength18.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
What the sources say
- Not checked — no full text of the sourcecites [18] Dudek, S. M. & Bear, M. F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-d-aspartate receptor blockade. Proc. Natl Acad. Sci. USA 89, 4363–4367 (1992) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“This was further confirmed with a different GluA2/3 antibody (Suppl. Table 2).”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One interpretation is that the concentration of vesicle priming proteins in NCs favors evoked fusion in these subregions of the AZ.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Homogeneity of variances was tested using an F-test and found to be similar between compared groups.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“For a uniform distribution, e.g. when all localizations were uniformly randomized within the alpha shape, ga(r) = 1 (Fig. 1d). Any heterogeneity will result in a ga(r) > 1.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Autocorrelation function (ACF) analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“If localization assemblies inside the two synaptic clusters organized in a similar pattern and opposed each other, gc(r) > 1. If either synaptic cluster had a uniform distribution of localizations (Fig. 3b) or the internal assemblies were not aligned (Fig. 3c), gc(r) = 1.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > 3D Pair cross-correlation function (PCF) analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since the information of synaptic cluster shape and overall density had been normalized, gc(r) was fully dependent on the internal organizations of the two synaptic clusters.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > 3D Pair cross-correlation function (PCF) analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This equation is derived from fitting MdNND with d in a series of simulations of uniformly distributed synaptic clusters with different densities.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Analysis of synaptic clusters
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“By rotating a 3D scatterplot of localizations of a selected potential synapse, we evaluated the data quality and selected only those with clear pre- and postsynaptic components (e.g. no nearby third cluster which may indicate two synapses in close proximity) for further analysis.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Analysis of synaptic clusters
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experimental protocols were approved by the University of Maryland, Baltimore School of Medicine Institutional Animal Care and Use Committee.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For comparison of two or more distributions, all samples were assessed for normality using Shapiro-Wilk or Kolmogorov-Smirnov tests.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Single molecule tracking was employed to remove the overcounted localizations from peaks lasting for more than one frame.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Single molecule localization and analysis
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This value was determined based on series of tests on >100 synapses to obtain the best synaptic cluster shape while avoiding dramatic changes in volume when individual localizations near the border were added or removed.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Analysis of synaptic clusters
plainn = 156- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In principal, we cannot completely exclude the possibility of overcounting, so a certain fraction of detected NCs are potentially artificial.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Nanocluster analysis
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sample sizes were determined based on numbers reported in previous studies.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical methods were used to predetermine sample size.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The average deviation of localized z-positions of immobilized fluorophores was 40–50 nm.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > 3D STORM Imaging
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experiments were performed on neurons 14–21DIV and repeated on 3 or more separate cultures unless otherwise specified.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Only molecules localized with an x-y precision <10 nm37, fitting R2 > 0.6, and comprising >200 photons were used for further analysis.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Single molecule localization and analysis
What the sources say
- Not checked — no full text of the sourcecites [37] Thompson, R. E., Larson, D. R. & Webb, W. W. Precise nanometer localization analysis for individual fluorescent probes. Biophys. J. 82, 2775–2783 (2002) source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These localization groups likely represent an overestimate of a single-dye-molecule localization spread.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Autocorrelation function (ACF) analysis
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“A synaptic cluster was only considered for analysis if the volume was between 2 × 10−3 μm3 and 30 × 10−3 μm3 (Cit.38), and contained an average density of > 8 × 103 localizations/μm3.”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Analysis of synaptic clusters
What the sources say
- Not matchedcites Cit.38
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Not matched
The paper relies on this without support.
The nanocolumn architecture observed in cultured hippocampal neurons and acute hippocampal slices is representative of small CNS synapses generally.
“This provides a simple organizational principle that may hold for many small, CNS synapses, and will have the largest influence at synapses that typically release only one vesicle following an AP.”
The paper relies on this without support.
Comparing the measured transsynaptic alignment to a uniform distribution of active zone and PSD proteins provides a valid estimate of the synaptic strength gain.
“the measured distribution with transsynaptic alignment gained 21.8 ± 0.5% in synaptic strength compared to a uniform distribution of AZ and PSD proteins (Extended Data Fig. 8), suggesting this synaptic architecture facilitates higher single vesicle response potency.”
The authors state this as an assumption.
The fraction of open channels at a postsynaptic pixel is directly proportional to its normalized local channel density.
“each jth pixel is weighted by its normalized local density LDj (i.e. the channel fraction is assumed to be directly proportional to the channel local density).”
The paper relies on this without support.
The number of photons detected in a pHuse event is proportional to the number of vesicles released.
“This mixture probability defined the lower estimate (72%) for the percentage of single stimulus evoked fusion arising from single vesicles.”
The authors state this as an assumption.
Release probability at a presynaptic pixel depends only on normalized RIM local density via the modeled piecewise sigmoidal function.
“we modeled the spatial likelihood of release as a piecewise sigmoidal function dependent on the normalized local RIM density”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Of particular interest is the finding that these clusters are juxtaposed across from presynaptic release site (251, 252, 260).”
From Synaptic memory and CaMKII (2023) · cites this paper as [251]
The cited source says what the claim attributes to it.
In the citing paper
“Remarkably, when the CTD of neuroligin 1 is included, it partitions with the AMPAR/TARPs but not with the NMDARs, reminiscent of nanocolumns in the PSD (251–253)”
From Synaptic memory and CaMKII (2023) · cites this paper as [251]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Ca2+ imaging and analysis
“a maximum intensity projection was made”
§ A transsynaptic nanocolumn aligns neurotransmitter release to receptors > Methods > Ca2+ imaging and analysis
“by averaging all image frames”
Citations
Cites
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Three-Dimensional Super-Resolution Imaging by Stochastic Optical Reconstruction Microscopy
Huang, B., Wang, W.-Q., Bates, M., & Zhuang, X. (2008) · Science · doi:10.1126/science.1153529 · Cited by 2,830
Precise Nanometer Localization Analysis for Individual Fluorescent Probes
Thompson, R. E., Larson, D. R., & Webb, W. W. (2002) · Biophysical Journal · doi:10.1016/s0006-3495(02)75618-x · Cited by 2,320
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De novo mutations in schizophrenia implicate synaptic networks
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“Single AP-evoked release was measured over 60 trials of (1) 1 s acquisition of baseline fluorescence, (2) stimulus, (3) 2.”
MethodCulturing hippocampal neurons.
Tanaka, H. (2002) · Folia Pharmacologica Japonica · doi:10.1254/fpj.119.163 · Cited by 1,141
Direct stochastic optical reconstruction microscopy with standard fluorescent probes
van de Linde, S., Löschberger, A., Klein, T., Heidbreder, M., Wolter, S., Heilemann, M., & Sauer, M. (2011) · Nature Protocols · doi:10.1038/nprot.2011.336 · Cited by 1,104
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Cited by
Sorted by citations
Items 301–400 of 675
Finding functions of phase separation in the presynapse
McDonald, N. A., & Shen, K. (2021) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2021.04.001 · Cited by 14
Imaging the endocannabinoid signaling system
Dudok, B., & Soltész, I. (2021) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2021.109451 · Cited by 18
Two forms of asynchronous release with distinctive spatiotemporal dynamics in central synapses
Malagón, G., Myeong, J., & Klyachko, V. A. (2023) · eLife · doi:10.7554/elife.84041 · Cited by 14
Clavet-Fournier, V., Lee, C., Wegner, W., Brose, N., Rhee, J., & Willig, K. I. (2023) · iScience · doi:10.1016/j.isci.2023.108679 · Cited by 19
“9 Thus, our data support the notion that synaptic activity can modulate a trans -synaptic structural correlation and alignment of molecular components.”
BackgroundMethodInfluentialActivity-Driven Synaptic Translocation of LGI1 Controls Excitatory Neurotransmission
Cuhadar, U., Calzado-Reyes, L., Pascual-Caro, C., Aberra, A. S., Ritzau‐Jost, A., Aggarwal, A., Ibata, K., Podgorski, K., Yuzaki, M., Geis, C., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2024.114186 · Cited by 17
Fukata, Y., Fukata, M., MacGillavry, H. D., Nair, D. K., & Hosy, E. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.2104-23.2024 · Cited by 18
Self-citationActomyosin Contractility in the Generation and Plasticity of Axons and Dendritic Spines
Mikhaylova, M., Rentsch, J., & Ewers, H. (2020) · Cells · doi:10.3390/cells9092006 · Cited by 17
“This PSD is organized in nanodomains and tightly apposed across the synaptic cleft to a corresponding synaptic vesicle release machinery in the pre-synapse [15,16].”
BackgroundRoles of type IIa receptor protein tyrosine phosphatases as synaptic organizers
Fukai, S., & Yoshida, T. (2020) · FEBS Journal · doi:10.1111/febs.15666 · Cited by 16
MAGUKs are essential, but redundant, in long-term potentiation
Chen, X., Fukata, Y., Fukata, M., & Nicoll, R. A. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2107585118 · Cited by 16
Correlative Assembly of Subsynaptic Nanoscale Organizations During Development
Sun, S.-Y., Li, X.-W., Cao, R., Zhao, Y., Sheng, N., & Tang, A. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.748184 · Cited by 16
“To quantify the heterogeneity within the synaptic cluster, we employed a normalized autocorrelation function (ga) (Veatch et al., 2012; Tang et al., 2016).”
BackgroundMethodInfluentialSelf-citationGuzikowski, N. J., & Kavalali, E. T. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111172 · Cited by 16
Gürth, C., Lima, M. A. D. R. B. F., Macarrón‐Palacios, V., Hubrich, J., Delgado, A. R. C., Mougios, N., Opazo, F., & D’Este, E. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.18.562700 · Cited by 16
“This is achieved by dynamically influencing the alignment of postsynaptic receptors with presynaptic release sites ( 16 ).”
BackgroundTrans-synaptic molecular context of NMDA receptor nanodomains
Anderson, M. C., Dharmasri, P. A., Damenti, M., Metzbower, S. R., Laghaei, R., Blanpied, T. A., & Levy, A. D. (2025) · Nature Communications · doi:10.1038/s41467-025-62766-y · Cited by 16
Self-citationSimilarity and Diversity of Presynaptic Molecules at Neuromuscular Junctions and Central Synapses
Takikawa, K., & Nishimune, H. (2022) · Biomolecules · doi:10.3390/biom12020179 · Cited by 16
“The RIM clusters were located within 40 nanometers of the synaptic vesicle fusion site, which was visualized using the fluorescent probe vGlut1-pHluorin-mCherry [106,107], indicating the fusion of vesicles with the membrane [6].”
BackgroundMethodInfluentialSilva, M., Tran, V., & Marty, A. (2023) · eLife · doi:10.7554/elife.91087 · Cited by 14
Kleindienst, D., Montanaro, J., Bhandari, P., Case, M. J., Fukazawa, Y., & Shigemoto, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186737 · Cited by 16
“Evoked transmission preferentially occurs at sites of Rab3-interacting molecule (RIM) nanoclusters and these nanoclusters are reported to align with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) in hippocampal neurons [9].”
BackgroundFeng, Z., Wu, X., & Zhang, M. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108622 · Cited by 16
“Photoactivated localization microscopy further confirmed that RIM density increased within 40 nm of these fusion sites (Tang et al., 2016).”
BackgroundInfluentialUltrastructural analysis of wild-type and RIM1α knockout active zones in a large cortical synapse
Lichter, K., Paul, M. M., Pauli, M., Schoch, S., Kollmannsberger, P., Stigloher, C., Heckmann, M., & Sirén, A.-L. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111382 · Cited by 15
How do you recognize and reconstitute a synaptic vesicle after fusion?
Chanaday, N. L., & Kavalali, E. T. (2017) · F1000Research · doi:10.12688/f1000research.12072.1 · Cited by 14
Midorikawa, M. (2018) · Neuroscience Research · doi:10.1016/j.neures.2018.01.008 · Cited by 15
Delgado, J. Y., & Selvin, P. R. (2018) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2018.00021 · Cited by 16
“The small intrasynaptic mobility may be required for the increase in density of AMPARs that become concentrated at the transsynaptic nanocolumns following LTP as has been observed for PSD95 (Tang et al., 2016).”
BackgroundAMPA receptors in the synapse: Very little space and even less time
Baranovic, J. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108711 · Cited by 14
“One of the consequences of these trans-synaptic interactions is precise alignment of AMPA receptors with the presynaptic glutamate release sites (Fukata et al., 2021; Haas et al., 2018; Tang et al., 2016).”
BackgroundEndocytic proteins: An expanding repertoire of presynaptic functions
Tehran, D. A., & Maritzen, T. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.01.004 · Cited by 14
Willems, J., & MacGillavry, H. D. (2022) · Scientific Reports · doi:10.1038/s41598-022-08746-4 · Cited by 14
“1b) and varied the localization densities (which influences the MNND) (Fig.”
BackgroundInfluentialSelf-citationEjdrup, A. L., Lycas, M. D., Lorenzen, N., Konomi-Pilkati, A., Herborg, F., Madsen, K. L., & Gether, U. (2022) · Nature Communications · doi:10.1038/s41467-022-32064-y · Cited by 14
Quantitative DNA-PAINT imaging of AMPA receptors in live neurons
Youn, Y., Lau, G. W., Lee, Y., Maity, B. K., Gouaux, E., Chung, H. J., & Selvin, P. R. (2023) · Cell Reports Methods · doi:10.1016/j.crmeth.2023.100408 · Cited by 19
“This immobile fraction of GluA1AMPARs exists in synaptic nanodomains where the receptors enrich and are potentially aligned to the presynaptic glutamate release site as reported.(17,39) The observations are consistent with previous reports, proving that AMPARs form nanometric organization without causing overexpressio…”
ResultActivity-dependent diffusion trapping of AMPA receptors as a key step for expression of early LTP
Nowacka, A., Getz, A. M., Bessa‐Neto, D., & Choquet, D. (2024) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2023.0220 · Cited by 21
“…of µM range) [97] and the concentration of glutamate rapidly drops with distance from the release site [98], the localization of AMPAR clusters facing release sites seemed a plausible novel mechanism to increase the probability of their activation [97], as it was demonstrated soon after [99].”
BackgroundInfluentialSumino, A., Sumikama, T., Zhao, Y., Flechsig, H., Umeda, K., Kodera, N., Konno, H., Hattori, M., & Shibata, M. (2024) · ACS Nano · doi:10.1021/acsnano.4c06295 · Cited by 14
Duplex Labeling and Manipulation of Neuronal Proteins Using Sequential CRISPR/Cas9 Gene Editing
Droogers, W. J., Willems, J., MacGillavry, H. D., & de Jong, A. P. H. (2022) · eNeuro · doi:10.1523/eneuro.0056-22.2022 · Cited by 17
Self-citationChen, X., Crosby, K. C., Feng, A. Y., Purkey, A., Aronova, M. A., Winters, C. A., Crocker, V. T., Leapman, R. D., Reese, T. S., & Dell’Acqua, M. L. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.1004154 · Cited by 14
“Our coordinate analysis of dSTORM localizations is conceptually similar to methods previously used to classify nanoscale organization at excitatory synapses (Tang et al., 2016), using a local-density calculation, high-density regions (HDRs) were defined by a cutoff determined by randomizing the experimental localizati…”
MethodMolecular mechanisms of AMPAR reversible stabilization at synapses
Bessa‐Neto, D., & Choquet, D. (2023) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2023.103856 · Cited by 12
Transport reliability on axonal cytoskeleton
Beiu, V. C., Rohatinovici, N. C., Dăuş, L., et al. (2017) · International Conference on Engineering of Modern Electric Systems · doi:10.1109/emes.2017.7980404 · Cited by 13
Polarity proteins: Shaping dendritic spines and memory
Voglewede, M. M., & Zhang, H. (2022) · Developmental Biology · doi:10.1016/j.ydbio.2022.05.007 · Cited by 14
Deficits in integrative NMDA receptors caused by Grin1 disruption can be rescued in adulthood
Venkatesan, S., Binko, M. A., Mielnik, C. A., Ramsey, A. J., & Lambe, E. K. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01619-y · Cited by 13
“Reduction and preservation of NMDAR function in extrasynaptic vs. synaptic regions respectively may involve a reorganization of nanodomain architecture or stability [56, 57].”
Intersectin and endophilin condensates prime synaptic vesicles for release site replenishment
Ogunmowo, T. H., Hoffmann, C., Patel, C., Pepper, R., wang, H., Gowrisankaran, S., Idel, J., Ho, A. S., Raychaudhuri, S., Maher, B. J., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02002-4 · Cited by 14
Hidalgo, S., Campusano, J. M., & Hodge, J. J. L. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01418-3 · Cited by 14
Tanaka, M., Sakaba, T., & Miki, T. (2021) · The Journal of Physiology · doi:10.1113/jp282235 · Cited by 16
“…demonstrated that docking site numbers matched with the numbers of supramolecular assemblies, such as Ca2+ channel, Munc13 and RIM nanoclusters (Tang et al. 2016; Miki et al. 2017; Pulido & Marty, 2017; Sakamoto et al. 2018), suggesting that the molecular nano-assemblies defined the regions…”
BackgroundNeurons as a model system for cryo-electron tomography
Zuber, B., & Lučić, V. (2022) · Journal of Structural Biology X · doi:10.1016/j.yjsbx.2022.100067 · Cited by 13
Gookin, S. E., Taylor, M. R. G., Schwartz, S. L., et al. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.852227 · Cited by 13
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Akter, Y., Jones, G. C., Daskivich, G. J., Shifflett, V., Vargas, K. J., & Hruska, M. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3002649 · Cited by 14
Hosokawa, T., & Liu, P.-W. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.795757 · Cited by 12
“Interestingly, a dualcolor three-dimensional dSTORM analysis revealed that the localization of the AMPAR nanodomain overlaps with the segregated cluster of PSD-95 at PSD and the presynaptic protein cluster of RIM1/2 (Tang et al., 2016), a marker for presynaptic active zones (Südhof, 2012).”
BackgroundEnhanced synaptic protein visualization by multicolor super-resolution expansion microscopy
Eilts, J., Reinhard, S., Michetschläger, N., Werner, C. D., & Sauer, M. (2023) · Neurophotonics · doi:10.1117/1.nph.10.4.044412 · Cited by 14
“40,41 Closer inspection of our expanded 2D and 3D four-color fluorescence images shows that synaptic vesicles close to the pre-synaptic membrane overlay with the RIM1/2 signals (Fig.”
BackgroundCationic peptides cause memory loss through endophilin-mediated endocytosis
Stokes, E. G., Vasquez, J. J., Azouz, G., Nguyen, M. H., Tierno, A. M., Zhuang, Y., Galinato, V. M., Hui, M., Toledano, M., Tyler, I., et al. (2025) · Nature · doi:10.1038/s41586-024-08413-w · Cited by 13
Phase Separation–Mediated Compartmentalization Underlies Synapse Formation and Plasticity
Wu, X., Shen, Z., & Zhang, M. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-040159 · Cited by 15
Illuminating Relationships Between the Pre- and Post-synapse
Sanderson, T. M., Georgiou, J., & Collingridge, G. L. (2020) · Frontiers in Neural Circuits · doi:10.3389/fncir.2020.00009 · Cited by 17
Rare germline variants in individuals diagnosed with schizophrenia within multiplex families
Li, S., DeLisi, L. E., & McDonough, S. I. (2021) · Psychiatry Research · doi:10.1016/j.psychres.2021.114038 · Cited by 12
Zebrafish neuromuscular junction: The power of N
Brehm, P., & Wen, H. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134503 · Cited by 12
“A number of studies have shown that key active zone proteins such as Rim, Munc13 and P/Q type calcium channels are not distributed randomly but rather form Nano-clusters (Holderith et al., 2012; Tang et al., 2016; Sakamoto et al., 2018).”
BackgroundSynaptic PSD-95 biology: from localization and interactors to N-terminus function
Alkaas, A., Kurup, P., Kanuru, S., Rommel, A. V., Singh, T., Patel, M. J., & Delgado, J. Y. (2025) · Journal of Neurophysiology · doi:10.1152/jn.00272.2025 · Cited by 16
Viard, J., Loe-Mie, Y., Daudin, R., Khelfaoui, M., Plançon, C., Boland, A., Tejedor, F. J., Huganir, R. L., Kim, E., Kinoshita, M., et al. (2022) · Life Science Alliance · doi:10.26508/lsa.202101205 · Cited by 12
Biophysical Modeling of Synaptic Plasticity
Lee, C. T., Bell, M. K., Bonilla-Quintana, M., & Rangamani, P. (2024) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-072123-124954 · Cited by 16
Choquet, D., Opazo, P., & Zhang, H. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00470-z · Cited by 11
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Funahashi, J., Tanaka, H., & Hirano, T. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00140 · Cited by 11
“Syp-SEP fluorescence change after the single pulse stimulation was analyzed using custom routines of MATLAB (Mathworks; RRID:SCR_001622) as described previously (Tang et al., 2016) with some modifications.”
BackgroundMethodResultInfluentialNanoscale organization of the pre-synapse: Tracking the neurotransmitter release machinery
Gormal, R. S., & Meunier, F. A. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.102576 · Cited by 11
Transient, nano-scale, liquid-like molecular assemblies coming of age
Kusumi, A., Tsunoyama, T. A., Suzuki, K. G. N., Fujiwara, T. K., & Aladağ, A. (2024) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2024.102394 · Cited by 12
Maschi, D., Gramlich, M. W., & Klyachko, V. A. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.650334 · Cited by 12
“Because the number of release sites per AZ vary widely across synapse population (in the range of 2-18 (Maschi and Klyachko, 2017; Sakamoto et al., 2018; Tang et al., 2016)), the model was formulated not to depend on the precise number of release sites, but rather on the gradient of release site Pr (central/peripheral…”
BackgroundInfluentialBang, E., Tobery, A. N., Montgomery, K. S., Fincher, A. S., Earnest, D. J., Murchison, D. A., & Griffith, W. H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.673155 · Cited by 11
Intracellular signaling mechanisms that shape postsynaptic GABAergic synapses
Jung, H., Kim, S., Ko, J., & Um, J. W. (2023) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2023.102728 · Cited by 11
Delling, J. P., Bauer, H. F., Gerlach-Arbeiter, S., Schön, M., Jacob, C., Wagner, J., Pedro, M. T., Knöll, B., & Boeckers, T. M. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02559-9 · Cited by 10
Mikuni, T., & Uchigashima, M. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14734 · Cited by 11
“Also, the localization of actin or AMPA receptors has been recently monitored in the context of spine structural dynamics using super-resolution microscopy, providing nanoscale, subspine resolution analysis of molecular dynamics during LTP (Frost, Shroff, Kong, Betzig, & Blanpied, 2010; Inavalli et al., 2019; Tang et…”
MethodActor-Engel, H. S., Schwartz, S. L., Crosby, K. C., Sinnen, B. L., Prikhodko, O., Ramsay, H. J., Bourne, J. N., Winborn, C. S., Lucas, A., Smith, K. R., et al. (2021) · eNeuro · doi:10.1523/eneuro.0416-21.2021 · Cited by 11
“…in the cross-correlation was 10nm, and the error threshold for the recalculation of the drift was five pixels. dSTORM analysis Coordinate analysis of our dSTORM data are conceptually similar to methods previously used to classify nanoscale organization at the excitatory synapse (Tang et al., 2016).”
MethodOptical tools to study the subcellular organization of GPCR neuromodulation
Jullié, D., Valbret, Z., & Stoeber, M. (2021) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2021.109408 · Cited by 11
Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis
Khan, S. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02916-1 · Cited by 11
The Altered Supramolecular Structure of Dopamine D2 Receptors in Disc1-deficient Mice
Onishi, T., Sakamoto, H., Namiki, S., & Hirose, K. (2018) · Scientific Reports · doi:10.1038/s41598-018-20090-0 · Cited by 10
Fluorescence Nanoscopy in Neuroscience
Wang, Y., Lin, J., Zhang, Q., Chen, X., Luan, H., & Gu, M. (2021) · Engineering · doi:10.1016/j.eng.2020.11.010 · Cited by 11
Church, E., Hamid, E., Zurawski, Z., Potcoava, M. C., Flores-Barrera, E., Caballero, A., Tseng, K. Y., & Alford, S. T. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0035-21.2021 · Cited by 9
Local BMP signaling: A sensor for synaptic activity that balances synapse growth and function
Vicidomini, R., & Serpe, M. (2022) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2022.04.001 · Cited by 10
Visualizing the trans-synaptic arrangement of synaptic proteins by expansion microscopy
Sachs, S., Reinhard, S., Eilts, J., Sauer, M., & Werner, C. D. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1328726 · Cited by 8
Alteration of synaptic protein composition during developmental synapse maturation
Kaizuka, T., & Takumi, T. (2024) · European Journal of Neuroscience · doi:10.1111/ejn.16304 · Cited by 13
“Nanoclusters of PSD-95 and AMPARs tend to be placed in front of synaptic vesicle-releasing sites marked with RIM1/2 (Tang et al., 2016).”
BackgroundLiouta, K., Lubas, M., Venugopal, V., Chabbert, J., Jeannière, C., Diaz, C., Munier, M., Tessier, B., Claverol, S., Favereaux, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53090-y · Cited by 9
Tuning synapse strength by nanocolumn plasticity
Xu, N., Chen, S.-Y., & Tang, A. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2024.12.009 · Cited by 10
Self-citationPrinciples and Design of Molecular Tools for Sensing and Perturbing Cell Surface Receptor Activity
Sescil, J., Havens, S. M., & Wang, W. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00582 · Cited by 12
Blaum, N., Ghelani, T., Götz, T., Chronister, K. S., Bengochea, M., Ceresnova, L., Christensen, C., Moulin, T. C., Kern, H. B., Thomas, U., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2514151122 · Cited by 6
Guerrero, A. A., & Turrigiano, G. G. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0807-25.2025 · Cited by 12
Computational modeling of trans-synaptic nanocolumns, a modulator of synaptic transmission
Li, X., Hémond, G., Godin, A. G., & Doyon, N. (2022) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2022.969119 · Cited by 10
“Nanocolumns are submicroscopic structures which span the presynaptic, synaptic, and postsynaptic spaces (Tang et al., 2016; Chen et al., 2018; Sarkar et al., 2022).”
InfluentialNoise-induced coexisting firing patterns in hybrid-synaptic interacting networks
Wang, X., Zhang, X., Zheng, M., Xu, L., & Xu, K. (2023) · Physica A Statistical Mechanics and its Applications · doi:10.1016/j.physa.2023.128591 · Cited by 9
Jung, J. H., Chen, X., & Reese, T. S. (2023) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2023.1123564 · Cited by 9
“A few super-resolution microscopy studies reported one to four nanodomains or nanomodules of PSD-95 (Fukata et al., 2013; Hruska et al., 2018) and about two nanodomains of PSD-95 (Tang et al., 2016) while zero to six nanodomains of AMPA receptors were reported (Nair et al., 2013), showing that the number of nanodomain…”
BackgroundInfluentialGustafsson, B., Ma, R., & Hanse, E. (2019) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2019.00007 · Cited by 9
“, 2015) as well as for the release and AMPA receptor locations (MacGillavry et al., 2013; Tang et al., 2016; Haas et al., 2018) has also indicated the importance of such close spatial organization.”
BackgroundInfluentialFluorescence Microscopy with Nanometer Resolution
Sahl, S. J., Schönle, A., & Hell, S. W. (2019) · Springer handbooks · doi:10.1007/978-3-030-00069-1_22 · Cited by 9
In vivo super-resolution of the brain – How to visualize the hidden nanoplasticity?
Willig, K. I. (2022) · iScience · doi:10.1016/j.isci.2022.104961 · Cited by 8
“…that pre-and postsynaptic proteins such as receptors or scaffolding proteinsformapatterneddistribution,whichischangedbyactivityandmightinfluencethesynapticstrengthby rearrangement or concerted alignment between pre-and postsynapse (Compans et al., 2016; Carvalhais et al., 2021; Tang et al., 2016).”
The Synaptic Basis of Activity-Dependent Eye-Specific Competition
Zhang, C., Yadav, S., & Speer, C. M. (2022) · Cell Reports · doi:10.1016/j.celrep.2023.112085 · Cited by 9
“44,45 To investigate whether SSDs in retinogeniculate synapses show developmental or eye-specific differences, we identified pre-/postsynaptic SSDs on the basis of voxel intensity distributions in 3D-aligned STORM images (Figure 4A, “image-based analysis”).”
In-Situ Structure and Topography of AMPA Receptor Scaffolding Complexes Visualized by CryoETPreprint
Held, R. G., Liang, J., Esquivies, L. R., Khan, Y. A., Wang, C., Azubel, M., & Brünger, A. T. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.19.619226 · Cited by 12
“…and PSD-95 form sub-synaptic nanoclusters, tens of nanometers in diameter within individual synapses ( 18 – 20 These nanoclusters are proposed to act as signaling hotspots, potentiating synaptic response amplitude by increasing receptor density opposite synaptic vesicle fusion sites ( 20 , 21 ).”
InfluentialInhibitory postsynaptic density from the lens of phase separation
Bai, G., & Zhang, M. (2022) · Oxford Open Neuroscience · doi:10.1093/oons/kvac003 · Cited by 8
“Importantly, the presynaptic RIM nanodomain is aligned with the postsynaptic nanodomains containing PSD-95-clustered AMPARs, forming trans-synaptic molecular nanocolumns [96].”
BackgroundPost-synaptic GABAA receptors potentiate transmission by recruiting CaV2 channels to their inputs
Zhao, J., Gao, L., Nurrish, S., & Kaplan, J. M. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113161 · Cited by 8
“At both glutamatergic and GABAergic synapses, pre-synaptic release sites are aligned with post-synaptic receptors in nanocolumns, 17,41 consistent with their transsynaptic linkage.”
BackgroundZhang, Y.-F., Wang, T., Cai, Y., Cui, T., Kuah, M., Vicini, S., & Wang, T. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1253669 · Cited by 7
“…dynamic modulations in the abundance and organization of various active zone components and calcium channels, following the inhibition of postsynaptic glutamate receptors in both Drosophila and mammalian systems (Tang et al., 2016; Bohme et al., 2019; Gratz et al., 2019; Ghelani et al., 2023).”
BackgroundInfluentialPadamsey, Z., Tong, R., & Emptage, N. J. (2019) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2019.00005 · Cited by 8
“Recent experimental evidence suggests that neurotransmitter release at a synapse is mediated by multiple, independent presynaptic release modules (Tang et al., 2016; Biederer et al., 2017).”
BackgroundMinehart, J. A., & Speer, C. M. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.615059 · Cited by 9
“, 2018) and SSDs containing receptors and critical synaptic machinery show activity-dependent changes in response to stimulation protocols for inducing synaptic potentiation, depression, and homeostatic plasticity (MacGillavry et al., 2013; Tang et al., 2016; Pennacchietti et al., 2017; Sinnen et al., 2017; Ferreira e…”
BackgroundImaging of spine synapses using super-resolution microscopy
Kashiwagi, Y., & Okabe, S. (2021) · Anatomical Science International · doi:10.1007/s12565-021-00603-0 · Cited by 9
Rapid astrocyte-dependent facilitation amplifies multi-vesicular release in hippocampal synapses
Myeong, J., & Klyachko, V. A. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111820 · Cited by 9
“23,43 We thus next ask if a subset of release sites is preferentially utilized during astrocyte-dependent facilitation.”
Kim, K., Yoon, J., Macks, C. P., Park, H., Youn, J., Lee, J.-U., An, M., Park, J., Ko, J., & Sohn, C. H. (2023) · ACS Nano · doi:10.1021/acsnano.2c10664 · Cited by 8
Practical Guidelines for Two-Color SMLM of Synaptic Proteins in Cultured Neurons
Yang, X., & Specht, C. G. (2020) · Neuromethods · doi:10.1007/978-1-0716-0532-5_9 · Cited by 8
Diaspro, A., Bianchini, P., Zanacchi, F. C., Lanzanò, L. L., Vicidomini, G., Oneto, M., Pesce, L., & Cainero, I. (2019) · Springer handbooks · doi:10.1007/978-3-030-00069-1_21 · Cited by 9
The molecular infrastructure of glutamatergic synapses in the mammalian forebrainPreprint
Peukes, J., Lovatt, C., Leistner, C., Boulanger, J., Morado, D. R., Fuller, M. J., Kukulski, W., Zhu, F., Komiyama, N. H., Briggs, J. A. G., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.19.432002 · Cited by 8
Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95Preprint
Dharmasri, P. A., DeMarco, E. M., Anderson, M. C., Levy, A. D., & Blanpied, T. A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.12.574705 · Cited by 8
“PSD-95 NCs align receptors with release sites to strengthen synaptic transmission (Ramsey et al., 2021; Tang et al., 2016).”
BackgroundInfluentialSelf-citationDynamic extracellular interactions with AMPA receptors
Goldschmidt, H. L., Barber, C. N., Renuse, S., Cutler, J. A., Kreimer, S. D., Bygrave, A. M., Meyers, D. J., Hale, W. D., Pandey, A., & Huganir, R. L. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2517436122 · Cited by 7
“Super - resolution analysis of synaptic nanodomains following cLTP has revealed that different synaptic proteins change their organization on different time scales following cLTP ( 37 , 60 ).”
Modification of the synaptic cleft under excitatory conditions
Tao-Cheng, J.-H., Moreira, S. L., Winters, C. A., Reese, T. S., & Döṣemeci, A. (2023) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2023.1239098 · Cited by 7
“Other transsynaptic assemblies aligning synaptic vesicle (SV) release sites to postsynaptic receptors (Martinez-Sanchez et al., 2021) are part of nano columns thought to influence synaptic efficacy (Tang et al., 2016).”
Chen, Y., Liu, S., Jacobi, A. A., Jeng, G., Ulrich, J. D., Stein, I. S., Patriarchi, T., & Hell, J. W. (2024) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2024.1291262 · Cited by 9
Midorikawa, M., Sakamoto, H., Nakamura, Y., Hirose, K., & Miyata, M. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114770 · Cited by 11
Monitoring of activity-driven trafficking of endogenous synaptic proteins through proximity labeling
Pascual-Caro, C., & de Juan‐Sanz, J. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002860 · Cited by 8
Metadata
- Authors
- Tang, A.-H., Chen, H., Li, T. P., Metzbower, S. R., MacGillavry, H. D., & Blanpied, T. A.
- Affiliations
- University of Maryland, Baltimore (US)
- Utrecht University (NL)
- Corresponding author
- Tang, Ai-Hui
- Blanpied, Thomas A.
- Venue
- Nature
- Published
- 2016-07-27
- Volume
- 536
- Issue
- 7615
- Pages
- 210-214
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5002394
- OpenAlex
- W2484055001
- Semantic Scholar
- 2675aa700769c280a18e88255a3108b615254736
- Cited by
- 677
- References
- 51
- Citations by year
- 2026: 56 · 2025: 58 · 2024: 83 · 2023: 62 · 2022: 79 · 2021: 94 · 2020: 61 · 2019: 58 · 2018: 69 · 2017: 48 · 2016: 8
- FWCI
- 29.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- National Institutes of Health (1s10od010352-01)
- National Institute of Mental Health (R01 MH080046, F30 MH102891, F30-MH105111, F31 MH105105, R37 MH080046)
- National Institute of General Medical Sciences (T32 GM-008181, R01 GM106000)
- National Institute of Neurological Disorders and Stroke (R01 NS-090644, NS090644)
- 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 › Biophysics › Advanced Fluorescence Microscopy Techniques
- Keywords
- synaptic vesicle fusion, active zone, nanoclusters, RIM, postsynaptic receptors, synaptic scaffolding proteins, synaptic plasticity, vesicle priming, hippocampal neurons, synaptic structure, localization microscopy, super-resolution microscopy
- MeSH terms
- Action Potentials, Animals, Male, Membrane Fusion, Microscopy, Synaptic Transmission, Neuronal Plasticity, Synapses, Receptors, N-Methyl-D-Aspartate, Receptors, AMPA, Neurotransmitter Agents, GTP-Binding Proteins, Rats, Post-Synaptic Density
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 2026-10-12, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-12 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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