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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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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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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- Load-bearing: passes — The paper’s conclusions depend on it.
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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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- 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
“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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- 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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
Ultrasensitive fluorescent proteins for imaging neuronal activity
Chen, T.-W., Wardill, T. J., Sun, Y., Pulver, S. R., Renninger, S. L., Baohan, A., Schreiter, E. R., Kerr, R. A., Orger, M. B., Jayaraman, V., et al. (2013) · Nature · doi:10.1038/nature12354 · Cited by 6,474
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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Dudek, S. M., & Bear, M. F. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4363 · Cited by 1,708
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · cited 1×
“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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Südhof, T. C. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.012 · Cited by 1,062
Cited by
Sorted by citations
Items 401–500 of 675
Cryo-electron tomographic investigation of native hippocampal glutamatergic synapsesPreprint
Matsui, A., Spangler, C. J., Elferich, J., Shiozaki, M., Jean, N., Zhao, X., Qin, M., Zhong, H., Yu, Z., & Gouaux, E. (2024) · eLife · doi:10.7554/elife.98458.3 · Cited by 40
“…that in excitatory, glutamatergic synapses, there is a transsynaptic organization of presynaptic and postsynaptic components that aligns sites of transmitter release and detection ( Chen et al., 2008 ; Tang et al., 2016 ; Tao et al., 2018 ; Martinez-Sanchez et al., 2021 ; Cole and Reese, 2023 ).”
BackgroundWhat We Can Learn From Cumulative Numbers of Vesicular Release Events
Miki, T. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00257 · Cited by 7
Dergachev, V. D., Yakovleva, E. E., Brusina, M., Bychkov, E., Piotrovskiy, L., & Shabanov, P. (2021) · Meditsinskiy sovet = Medical Council · doi:10.21518/2079-701x-2021-12-406-412 · Cited by 2
Nanoscale reorganisation of synaptic proteins in Alzheimer's disease
Zhu, W., Yang, X., Gou, X., Fu, S., Chen, J., Gao, F., Shen, Y., Bi, D., & Tang, A. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12924 · Cited by 6
“02 software as described previously.([17,19])”
InfluentialSelf-citationLiquid Active Zones for Controlling the Phases of Synaptic Transmission
Emperador-Melero, J., & Kaeser, P. S. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.020 · Cited by 6
Stable and Flexible Synaptic Transmission Controlled by the Active Zone Protein Interactions
Mochida, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111775 · Cited by 7
“The AZ of hippocampal excitatory synapses contains several clusters of the scaffold RIM, and these clusters mark individual release sites [6].”
BackgroundQuantitative Imaging With DNA-PAINT for Applications in Synaptic Neuroscience
Unterauer, E. M., & Jungmann, R. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.798267 · Cited by 7
Wallis, T. P., Jiang, A., Hou, H., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.08.459552 · Cited by 7
Uncovering brain tissue architecture across scales with super-resolution light microscopyPreprint
Michalska, J. M., Lyudchik, J., Velicky, P., Korinkova, H., Watson, J. F., Cenameri, A., Sommer, C., Venturino, A., Rössler, K., Czech, T., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.17.504272 · Cited by 7
Shohayeb, B., Sempert, K., Wallis, T. P., Meunier, F. A., Durisic, N., O’Brien, E. A., Flores, C., & Cooper, H. M. (2024) · iScience · doi:10.1016/j.isci.2024.110621 · Cited by 6
Ducrot, C., Drouet, A., Tessier, B., Desquines, C., Cloâtre, T., Mazzouzi, R.-C., Levet, F., Favereaux, A., Letellier, M., & Thoumine, O. R. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2411669122 · Cited by 9
“…imaging showed that bAP - NLGN1 nanodomains were in proximity to GFP - NRXN1 β and RIM1/2 clusters, likely forming trans - synaptic nanocolumns ( 48 , 49 ). bAP - NLGN1 nanodomains did not occupy the center of synapses as LRRTM2 ( 25 , 69 , 70 ), or their periphery as N - cadherin or SynCAM1 (…”
Synapse-specific and plasticity-regulated AMPA receptor mobility tunes synaptic integration
Nowacka, A., Getz, A. M., Zieger, H. L., Malivert, M., Bessa‐Neto, D., Augusto, E., Breillat, C., Daburon, S., Lemoigne, C., Marais, S., et al. (2026) · Neuron · doi:10.1016/j.neuron.2025.12.004 · Cited by 10
Grasskamp, A. T., Jusyte, M., McCarthy, A. W., Götz, T., Ditlevsen, S., & Walter, A. M. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1129417 · Cited by 6
“This was improved by the development of elegant live-imaging approaches to track synaptic activity with high spatial resolution (Peled and Isacoff, 2011; Melom et al., 2013; Peled et al., 2014; Reese and Kavalali, 2016; Tang et al., 2016; Sakamoto et al., 2018; Farsi et al., 2021).”
MethodZhang, H., Lei, M., Zhang, Y., Li, H., He, Z., Xie, S., Zhu, L., Wang, S., Liu, J., Li, Y., et al. (2024) · Science Advances · doi:10.1126/sciadv.adi7024 · Cited by 7
Phase separation in the multi-compartment organization of synapses
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“…machinery components: i) RIM - binding protein (Rbp), which connects release sites to the scaffolding protein Bruchpilot (Brp), ii) Unc - 13, a regulator of synaptic vesicle priming, and iii) Cacophany (Cac), the voltage - gated Ca 2+ channel that couples the AP to transmitter release ( 13 – 17 ).”
Rethinking calcium profiles around single channels: the exponential and periodic calcium nanodomains
Mironov, S. L. (2019) · Scientific Reports · doi:10.1038/s41598-019-53095-4 · Cited by 6
Super-resolution imaging to reveal the nanostructure of tripartite synapses
Aleksejenko, N., & Heller, J. P. (2021) · Neuronal Signaling · doi:10.1042/ns20210003 · Cited by 7
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Nanocolumns at the heart of the synapse
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Simple multi-color super-resolution by X10 microscopy
Truckenbrodt, S., & Rizzoli, S. O. (2020) · Methods in cell biology · doi:10.1016/bs.mcb.2020.04.016 · Cited by 6
Nanoscaled RIM clustering at presynaptic active zones revealed by endogenous tagging
Mrestani, A., Dannhäuser, S., Pauli, M., Kollmannsberger, P., Hübsch, M., Morris, L., Langenhan, T., Heckmann, M., & Paul, M. M. (2023) · Life Science Alliance · doi:10.26508/lsa.202302021 · Cited by 7
Gβγ SNARE Interactions and Their Behavioral Effects
Alford, S. T., Hamm, H. E., Rodriguez, S., & Zurawski, Z. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2531-x · Cited by 6
Structural insights into leucine-rich repeat-containing synaptic cleft molecules
Yamagata, A., & Fukai, S. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.01.001 · Cited by 6
Tan, R. P. A., Kozlova, I., Su, F., Sah, S. K., Keable, R., Hagan, D. W., Bustamante, S., Du, X., Osborne, B., Turner, N. A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.08.479601 · Cited by 6
“Cell adhesion molecules are involved in organizing the presynaptic nanoarchitecture required for highly regulated neurotransmitter release (Tang et al., 2016).”
BackgroundSequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortexPreprint
Morris, K., Bulovaite, E., Kaizuka, T., Schnorrenberg, S., Adams, C. T., Komiyama, N. H., Mendive‐Tapia, L., Grant, S. G. N., & Horrocks, M. H. (2024) · eLife · doi:10.7554/elife.99303 · Cited by 6
eSylites: Synthetic Probes for Visualization and Topographic Mapping of Single Excitatory Synapses
Huhn, C., Ho, S., Schulte, C., Khayenko, V., Hemmen, K., Peulen, T.-O., Wiessler, A.-L., Bothe, S., Bej, A., Talucci, I., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c00772 · Cited by 6
Phase separation instead of binding strength determines target specificities of MAGUKs
Chen, Y., Ma, C., Shen, Z., Chen, S., Zhu, S., Jia, B., Dang, S., & Zhang, M. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01925-0 · Cited by 5
“Synaptic adhesion molecules such as N-cadherins, neurexins and neuroligins have critical roles in aligning the presynaptic and postsynaptic compartments to ensure proper signal transmission speed and strength initiated by presynaptic released neurotransmitters 2–11 .”
Afferent convergence to a shared population of interneuron AMPA receptors
Pennock, R. L., Coddington, L. T., Yan, X. E., Overstreet‐Wadiche, L., & Wadiche, J. I. (2023) · Nature Communications · doi:10.1038/s41467-023-38854-2 · Cited by 5
Toxicity of nanoparticles onto plants: Overview of the biochemical and molecular mechanisms
Fattahi, N., Tabrizi, B. H., Rani, S., Sadeghi, Z., Dehghanian, Z., Lajayer, B. A., & van Hullebusch, E. D. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-90774-3.00002-7 · Cited by 5
STORM Super-Resolution Imaging of CB1 Receptors in Tissue Preparations
Zöldi, M., & Katona, I. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2728-0_36 · Cited by 5
Regulation of Presynaptic Release Machinery by Cell Adhesion Molecules
Uchigashima, M., Hayashi, Y., & Futai, K. (2023) · Advances in neurobiology · doi:10.1007/978-3-031-34229-5_13 · Cited by 5
Kinetic study of membrane protein interactions: from three to two dimensions
Adrien, V., Reffay, M., Taulier, N., et al. (2024) · Scientific Reports · doi:10.1038/s41598-023-50827-5 · Cited by 5
Cluster parameter-based DBSCAN maps for image characterization
Bíró, P., Kovács, B. B. H., Novák, T., & Erdélyi, M. (2025) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2025.02.037 · Cited by 6
AMPA and GABAA receptor nanodomains assemble in the absence of synaptic neurotransmitter release
Ramsay, H. J., Gookin, S. E., Ramsey, A. M., Kareemo, D. J., Crosby, K. C., Stich, D., Olah, S. S., Actor-Engel, H. S., Smith, K. R., & Kennedy, M. J. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1232795 · Cited by 5
“In TeNT-silenced presynaptic terminals, the active zone marker RIM1 formed SSDs that were smaller and more numerous than controls, but which remained in close apposition to postsynaptic AMPAR SSDs.”
BackgroundMethodInfluentialMiklosi, A. G., Favero, G. D., Marko, D., Harkany, T., & Lübec, G. (2018) · PROTEOMICS · doi:10.1002/pmic.201800139 · Cited by 5
Super-Resolution STED and STORM/PALM Microscopy for Brain Imaging
Egger, B., & Sprecher, S. G. (2018) · Progress in optical science and photonics · doi:10.1007/978-981-10-9020-2_12 · Cited by 6
Transcriptional changes in response to ketamine ester-analogs SN 35210 and SN 35563 in the rat brain
Jacobson, G. M., Voss, L. J., Klockars, A., Bird, S., Dimitrov, I., Denny, W. A., Olszewski, P. K., Sleigh, J. W., & Harvey, M. G. (2019) · BMC Genomics · doi:10.1186/s12864-019-5649-6 · Cited by 5
Rapid homeostatic modulation of transsynaptic nanocolumn ringsPreprint
Muttathukunnel, P., Frei, P., Perry, S., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.15.448550 · Cited by 5
Distinct nano-structures support a multifunctional role of actin at presynapses
Bingham, D., Wernert, F., Costa Moura, J. D., Boroni-Rueda, F., van Bommel, N., Caillol, G., Papandréou, M.-J., & Leterrier, C. (2022) · doi:10.1101/2022.05.18.492480 · Cited by 5
“…further refinements, like the formation of cross-synaptic nanocolumns that align the release machinery to the clusters of postsynaptic receptors (Tang et al., 2016) – although it should be noted that recent works hints at a primary role of the presynaptic side in organizing nanocolumns (Ramsey…”
BackgroundPresynaptic α2δs specify synaptic gain, not synaptogenesis, in the mammalian brain
Milanick, W., Li, J., Thomas, C. I., Al-Yaari, M., Guerrero‐Given, D., Kamasawa, N., & Young, S. M. (2025) · Neuron · doi:10.1016/j.neuron.2025.04.013 · Cited by 5
“40,41 Analysis of RIM1/2 levels and clustering revealed no difference between the Cacna2d1 ,2,3 (cid:0) / (cid:0) vs. Cacna2d1,2,3 +/+ calyces (Figures 3A–3E).”
InfluentialLőrincz, A., Ashaber, M., & Nusser, Z. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0645-25.2025 · Cited by 4
“The observed spatial arrangement of these proteins, including the clustering of Munc13-1 and GluA2, mirrored fi ndings obtained in rodents (Masugi-Tokita and Shigemoto, 2007; Tang et al., 2016; Szoboszlay et al., 2017; Sakamoto et al., 2018; Aldahabi et al., 2022).”
Synaptobrevin-2 disease variants reveal spatial constraints within the presynaptic active zone
Guzikowski, N. J., Bagatelas, E. D., Shin, O., Khan, Y. A., Esquivies, L. R., Alten, B., Brünger, A. T., & Kavalali, E. T. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2507347122 · Cited by 4
“Seven of the nine variants assessed display negative synaptic phenotypes that largely downregulate release across all modes of neurotransmission.”
Orchestrating synaptic strength by neuroligin-confined nanoscale organization
Han, Y., Dai, X., & Zhang, B. (2026) · Molecules and Cells · doi:10.1016/j.mocell.2026.100319 · Cited by 5
Review of imaging buffers used in stochastic optical reconstruction microscopy
Wang, C., Sun, Z., & Ma, D. (2024) · Chinese Chemical Letters · doi:10.1016/j.cclet.2024.110677 · Cited by 4
Synaptic Plasticity in the Hippocampus
Bliss, T., Collingridge, G. L., Cooke, S. F., Georgiou, J., & Morris, R. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780190065324.003.0010 · Cited by 4
Design and structural characterisation of olfactomedin-1 variants as tools for functional studies
Pronker, M. F., van den Hoek, H., & Janssen, B. J. C. (2019) · BMC Molecular and Cell Biology · doi:10.1186/s12860-019-0232-1 · Cited by 5
Westra, M., & MacGillavry, H. D. (2022) · Membranes · doi:10.3390/membranes12070650 · Cited by 5
“Subsynaptic domains enriched in glutamate receptors and scaffolding molecules were found to be aligned with the presynaptic glutamate release to optimize synaptic transmission, which emphasizes the importance of the heterogeneous organization of the neuronal membrane [42,43].”
BackgroundSelf-citationNanoscale Reorganization of Glutamate Receptors Underlies Synaptic Plasticity and Pathology
Chen, J.-H., & Tang, A. (2024) · Neuroscience Bulletin · doi:10.1007/s12264-024-01180-8 · Cited by 4
Self-citationSingle-Molecule-Resolution Approaches in Synaptic Biology
Sun, C. (2024) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.3c08026 · Cited by 3
Chapman, C. A., Povysheva, N. V., Tarr, T. B., Nuwer, J. L., Meriney, S. D., Johnson, J. W., & Jacob, T. C. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1624813 · Cited by 4
“This was followed by secondary antibody incubation and DAPI nuclear staining.”
Jackson, R. E., Compans, B., & Burrone, J. (2022) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2022.830583 · Cited by 5
Digitalizing neuronal synapses with cryo-electron tomography and correlative microscopy
Liu, Y.-T., & Tao, C.-L. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.102595 · Cited by 7
On Reliability of 3D Hammock Networks
Rohatinovici, N.-C., Proștean, O., & Bălaş, V. E. (2018) · IEEE International Symposium on Applied Computational Intelligence and Informatics (SACI) · doi:10.1109/saci.2018.8441003 · Cited by 4
“Of course the reliability of synapses is left out but there are some fresh results in [23] – [24] that probably will contribute in answering these open questions.”
BackgroundA Quantitative Perspective of Alpha-Synuclein Dynamics – Why Numbers Matter
Specht, C. G. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.753462 · Cited by 3
Active zone compaction in presynaptic homeostatic potentiationPreprint
Mrestani, A., Kollmannsberger, P., Pauli, M., Repp, F., Kittel, R. J., Eilers, J., Doose, S., Sauer, M., Sirén, A., Heckmann, M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/802843 · Cited by 5
“RIM clusters with diameters of ~80 nm were described in hippocampal neurons and show remarkable reorganization during synaptic plasticity (Tang et al., 2016).”
BackgroundInfluentialFunctional Architecture of the Synaptic Transducers at a Central Glutamatergic SynapsePreprint
Brockmann, M. M., Toulmé, E., Grasskamp, A. T., Trimbuch, T., Südhof, T. C., Walter, A. M., & Rosenmund, C. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.12.25.424391 · Cited by 3
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Self-citationZhang, J., Vaidya, R. M., Pendharkar, R., Chung, H. J., & Selvin, P. R. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.15.603616 · Cited by 7
“42 Importantly, using the quantitative analysis power of ISEPLA, we distinguished nanodomains and nanomodules as different synaptic nanostructures inside spines.”
Synaptic scaffold protein PSD-95: a therapeutic target for Alzheimer’s disease
Fan, X., Wang, H., Ping, J., Li, M., Gu, J., & Qian, W. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117401 · Cited by 8
Kuo, L. M. S., Liu, P.-W., Arizono, M., & Hayashi, Y. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.0871-25.2025 · Cited by 3
Ranjan, M., Lin, K., Mueller, B. D., Wojcik, S. M., Lohse, M., Südhof, T. C., Jørgensen, E. M., Neher, E., Lipstein, N., Brose, N., et al. (2026) · Science Advances · doi:10.1126/sciadv.aea0449 · Cited by 3
“Munc13-1 nanoclusters spatially overlap with RIM1/2, which is preferentially localized near SV release sites ( 76 ), whereas the central location of BSN nanoclusters within AZs is consistent with its proposed role as a structural scaffold.”
Decreased Water Mobility Contributes To Increased α‐Synuclein Aggregation**
Stephens, A. D., Kölbel, J., Moons, R., et al. (2022) · Angewandte Chemie · doi:10.1002/ange.202212063 · Cited by 3
Organizing the synaptic junctions
Zhou, Q. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104716 · Cited by 4
“It will also be interesting to see if other multiple-domain SAMs adopt different global 3D conformations to organize nanostructures including trans-cellular nanocolumns (9, 10).”
BackgroundPresynaptic Cytomatrix Proteins
Jin, Y., & Zhai, R. G. (2023) · Advances in neurobiology · doi:10.1007/978-3-031-34229-5_2 · Cited by 3
Actomyosin-mediated inhibition of synaptic vesicle release under CB1R activation
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Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex
Morris, K., Bulovaite, E., Kaizuka, T., Schnorrenberg, S., Adams, C. T., Komiyama, N. H., Mendive‐Tapia, L., Grant, S. G. N., & Horrocks, M. H. (2024) · eLife · doi:10.7554/elife.99303.3 · Cited by 4
Benson, D. L. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0743-19.2019 · Cited by 3
“…that can approach 10 nm. High-resolution examination of synaptic proteins is revealing a transsynaptic, modular organization (Dani et al., 2010; Perez de Arce et al., 2015; Tang et al., 2016; Biederer et al., 2017; Hruska et al., 2018) that is evident in cryo-ET (Perez de Arce et al., 2015).”
BackgroundNon-microtubule tubulin-based backbone and subordinate components of postsynaptic density lattices
Suzuki, T., Terada, N., Higashiyama, S., Kametani, K., Shirai, Y., Honda, M., Kai, T., Li, W., & Tabuchi, K. (2021) · Life Science Alliance · doi:10.26508/lsa.202000945 · Cited by 3
Gogoi, P., Shiozaki, M., & Gouaux, E. (2022) · PLoS ONE · doi:10.1371/journal.pone.0271799 · Cited by 2
Super-resolution imaging of synaptic scaffold proteins in rat hippocampal neurons
Guzikowski, N. J., & Kavalali, E. T. (2023) · STAR Protocols · doi:10.1016/j.xpro.2023.102080 · Cited by 3
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“Alternatively, one might speculate about additional proteins, different interaction surfaces taken, and transsynaptic columns ( Tang et al., 2016 ).”
BackgroundThivaios, S., Schwenk, J., Bréchet, A., Boudkkazi, S., Sethumadhavan, N., Henneken, P., Miura, E., Hayashi, A., Kocylowski, M. K., Haupt, A., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-77377-4 · Cited by 3
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“25 These supercomplexes then assemble into larger multiprotein complexes, which ultimately combine into NCs to form the PSD. 26 However, it is still unclear whether all these assembly stages occur within the synapse itself, which limits our understanding of how synaptic structure and function are…”
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Quantitative synapse analysis for cell-type specific connectomicsPreprint
Kuljis, D. A., Zemoura, K., Telmer, C. A., Lee, J., Park, E., Ackerman, D. S., Xu, W., Watkins, S. C., Arnold, D. B., Bruchez, M. P., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/386912 · Cited by 3
“Indeed, it is unclear for larger synapses whether these should be counted as a single synapse with multiple active sites and post-synaptic specializations (Tang et al., 2016), or combined into one large synapse (such as the giant synapses observed at the Calyx of Held).”
BackgroundPribbenow, C., Chen, Y., Heim, M. ‐., Laber, D., Reubold, S., Reynolds, E., Balles, I. S., Suárez-Grimalt, R., Rauch, C., Rösner, J., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.01.450776 · Cited by 3
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. (2024) · eLife · doi:10.7554/elife.100335 · Cited by 5
“These subsynaptic regions with higher concentrations of ionotropic glutamate receptors were reminiscent of receptor ‘nanodomains’ detected by super-resolution microscopy ( Broadhead et al., 2016 ; Dani et al., 2010 ; MacGillavry et al., 2013 ; Nair et al., 2013 ; Tang et al., 2016 ).”
InfluentialOne-step induction of human GABAergic neurons promotes presynaptic development & synapse maturationPreprint
van Voorst, T. W., van Boven, M. A., Marinus, K. I., Colon, J., Schretzmeir, J., Haag, C., Toonen, R. F. G., Koopmans, F., Ward, M. E., Smit, A. B., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.30.662293 · Cited by 3
Resolving endogenous protein organization in cells with nanometer precisionPreprint
Eilts, J., Jungblut, M., Helmerich, D. A., Sachs, S., Werner, C. D., Bogaciu, C.-A., Shaib, A., Rizzoli, S. O., Kollmannsberger, P., Doose, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.11.669713 · Cited by 3
“Using immunolabeling and d STORM it was shown that both RIM and Munc13-1 form discrete nanoclusters at the presynapse that could represent the postulated template for SV docking ( 52,53 ).”
The molecular infrastructure of glutamatergic synapses in the mammalian forebrain
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. (2025) · eLife · doi:10.7554/elife.100335.3 · Cited by 2
Polarized ATP synthase in synaptic mitochondria induced by learning and plasticity signals
Hu, Y., Wang, X., Liu, K., Xiong, S., Cai, B., Guan, J., Gu, M., & Xie, H. B. (2025) · Communications Biology · doi:10.1038/s42003-025-08963-3 · Cited by 4
Subcellular Structures in Native Hippocampal Synapses Revealed by Cryo-electron Tomography
Tian, C.-L., Qi, L., Lu, Z.-H., Liu, S., Gu, M., Huang, W.-L., Yan, Y.-T., Liu, Y., Wu, J., Wang, P., et al. (2026) · Neuroscience Bulletin · doi:10.1007/s12264-025-01569-z · Cited by 4
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Scales of Postsynaptic Nanostructure: Molecules, Nanoclusters, and Nanodomains
Damenti, M., Levy, A. D., & Blanpied, T. A. (2026) · Advances in neurobiology · doi:10.1007/978-3-032-12594-1_7 · Cited by 2
Self-citationTranssynaptic linking of calcium channels and postsynaptic receptors at a dyadic synapse
Zhao, J., Ardiel, E. L., Nurrish, S., & Kaplan, J. M. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2603452123 · Cited by 2
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Resolving endogenous protein organization in cells with nanometer resolution
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Lack of support for surface diffusion of postsynaptic AMPARs in tuning synaptic transmission
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Two-dimensional molecular condensation in cell signaling and mechanosensing
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“Their inter- and intramolecular interactions drive the formation of MLOs, which facilitates the release of neurotransmitter vesicles from the presynaptic neuron [69].”
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Charting the nanotopography of inner hair cell synapses using MINFLUX nanoscopy
Kapoor, R., Kim, H., Garlick, E., Lima, M. A. D. R. B. F., Esch, K., Ruhwedel, T., Möbius, W., Wolf, F., & Moser, T. (2025) · Science Advances · doi:10.1126/sciadv.ady4344 · Cited by 2
“Moreover, studies at CNS synapses have shown nano-clusters of presynaptic AZ components to be tightly aligned with postsynaptic scaffold proteins and receptor nanoclusters, suggesting transsynaptic “nanocolumns” that may contribute to synaptic efficiency at these synapses ( 23 ).”
Postsynaptic densities fragment into subcomplexes upon sonication
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Hemisynapse Formation Between Target Astrocytes and Cortical Neuron Axons in vitro
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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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