The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index; 10 of the 34 sources its claims cite were checked for support.
Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons
Open accessAbstract
Dendritic spines serve as preferential sites of excitatory synaptic connections and are pleomorphic. To address the structure-function relationship of the dendritic spines, we used two-photon uncaging of glutamate to allow mapping of functional glutamate receptors at the level of the single synapse. Our analyses of the spines of CA1 pyramidal neurons reveal that AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors are abundant (up to 150/spine) in mushroom spines but sparsely distributed in thin spines and filopodia. The latter may be serving as the structural substrates of the silent synapses that have been proposed to play roles in development and plasticity of synaptic transmission. Our data indicate that distribution of functional AMPA receptors is tightly correlated with spine geometry and that receptor activity is independently regulated at the level of single spines.
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TL;DR
Using two-photon uncaging of a newly developed caged glutamate, this study mapped functional AMPA receptors on individual dendritic spines of hippocampal CA1 pyramidal neurons. It finds that AMPA receptor expression is tightly correlated with spine-head geometry, with mushroom spines bearing many receptors and thin spines/filopodia few, suggesting independent regulation at single spines.
Key findings
- AMPA-type glutamate receptors are abundant in mushroom spines (up to 150/spine) but sparsely distributed in thin spines and filopodia; thin spines and filopodia may serve as structural substrates of silent synapses.
- Glutamate sensitivity of individual spines correlated strongly with spine-head volume: correlation coefficient r = 0.69–0.90 (0.80 ± 0.07; n = 9) within one dendrite, 0.89 in one example, and 0.77 for the average of 9 dendrites; correlation with spine length was weak and negative (r = 0.30).
- Nonstationary fluctuation analysis estimated 46–147 AMPA receptors in mushroom spines (82 ± 31; mean ± s.d., n = 8), with single-channel currents of 0.4–0.8 pA (0.6 ± 0.1 pA); estimated opening probability was 0.27, suggesting postsynaptic AMPA receptors are not saturated by glutamate from a single vesicle.
- Autocorrelation analysis along dendrites showed no correlation even in neighboring spines for glutamate sensitivities or spine-head volumes, suggesting AMPA receptor expression is controlled independently at the level of individual spines.
Methods
- Two-photon uncaging of MNI-glutamate combined with whole-cell patch-clamp electrophysiology and fluorescence imaging in cultured hippocampal neurons and acute hippocampal slices from rats (cultured neurons from P1 Wistar rats, used at 17–25 days; slices from 15–22 day old Sprague–Dawley rats unless otherwise stated; some young animals 7–9 days old).
- Functional mapping used pseudorandom scanning at 0.33 μm lateral intervals and z-axis sections separated by 0.8 μm, recording 2pEPSCs at −70 mV; spine-head volume was estimated from fluorescence images, and autocorrelation and nonstationary fluctuation analysis (with 0.1 mM cyclothiazide) were used.
- Analysis included kinetic/diffusion modeling of glutamate concentration and AMPA receptor opening, correlation coefficients, coefficients of variation, and estimation of receptor number and single-channel current.
Limitations
- Stated in the paper: the mechanism by which spine-head volume affects AMPA receptor trafficking remains to be determined, and whether thin spines, filopodia, and dendritic shafts transform into thicker spines after long-term potentiation is unknown. Spatial resolution in slices was slightly reduced (0.6 μm laterally and 1.4 μm axially) because of the lower numerical aperture lens, so dendrites with relatively sparse spines (~1 spine/μm) were studied; correlation values were reduced by channel noise (CV ~0.08) and sampling error (CV = 0.1).
- Evident from the text: experiments were performed at room temperature (23–25°C), in cultured neurons or acute slices from juvenile rats, and the main structure–function relationship is correlational rather than causal; some analyses relied on small samples (e.g., n = 7–9 dendrites, n = 8 for fluctuation analysis).
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10 of 34 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Nevertheless, two-photon excitation of MNI-glutamate permits the functional mapping of glutamate sensitivity with a spatiotemporal resolution similar to that achieved by activation of presynaptic terminals (~0.4μm and ~0.1 ms)28.”
What the sources say
- Could not verifycites [28] Rusakov, D. A. & Kullmann, D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J. Neurosci. 18, 3158–3170 (1998). sourceExperimental — accuracy not yet measured
The Synaptic currents and Activation of extrasynaptic receptors sections discuss modeled glutamate diffusion and receptor activation at distances around 400–465 nm; they do not describe the resolution of functional mapping. Searches for MNI-glutamate, two-photon excitation, and the claimed 0.1 ms resolution found no passage addressing the comparison with presynaptic-terminal activation. Page numbers were not available in our copy. (LLM, conf=0.76)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This observation suggests that the expression of AMPA receptors is controlled independently at a level of the individual spine, consistent with the classical notion that a single spine may behave as an independent chemical compartment to regulate synaptic transmission13, 14.”
What the sources say
- Partly supportedcites [13] 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 (p. 2983) proposes that constricted spine necks might limit diffusion to neighboring synapses, supporting the cited notion of a spine as a possible chemical compartment. The discussion of spine geometry and synaptic efficacy (page not specified in our copy) likewise treats compartmentation as a possibility. Neither passage establishes that AMPA-receptor expression is controlled independently at each spine. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [14] Yuste, R. & Denk, W. Dendritic spines as basic functional units of neuronal integration. Nature 375, 682–684 (1995). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In addition, our study suggests that thin spines and filopodia may be postsynaptic components of silent synapses28, 32, 34, 44.”
What the sources say
- Could not verifycites [28] Rusakov, D. A. & Kullmann, D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J. Neurosci. 18, 3158–3170 (1998). sourceExperimental — accuracy not yet measured
The Activation of extrasynaptic receptors section discusses NMDA-receptor activation at neighboring synapses and notes that dendritic spines may change shape, but does not identify thin spines or filopodia as components of silent synapses. Searches for “filopodia,” “thin spines,” and “silent synapses” found no passage making that connection; silent synapses appear in the References. (LLM, conf=0.74)
- Not checked — no full text of the sourcecites [32] Gomperts, S. N., Rao, A., Craig, A. M., Malenka, R. C. & Nicoll, R. A. Postsynaptically silent synapses in single neuron cultures. Neuron 21, 1443–1451 (1998). source
- Not checked — no full text of the sourcecites [34] Durand, G. M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996). source
- Partly supportedcites [44] Fiala, J. C., Feinberg, M., Popov, V. & Harris, K. M. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J. Neurosci. 18, 8900–8911 (1998). sourceExperimental — accuracy not yet measured
The Results report synapses on filopodia, and the Analysis describes how the postsynaptic process was identified as a spine or filopodium. The paper also mentions thin spines, but our copy does not identify synapses on either structure as silent; that qualification is unsupported. (LLM, conf=0.82)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Regions of glutamate sensitivity tended to be asymmetrically localized to one portion of a spine (Figs. 3h and 4c–j), consistent with the predominant localization of AMPA receptors within PSDs with a diameter of 0.1 to 0.5μm13, 19, 20.”
What the sources say
- Partly supportedcites [13] 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 citation follows the sentence’s PSD explanation, while the asymmetric glutamate-sensitivity observation is presented as the citing paper’s own finding. In “Relationships between hippocampal spine geometry and,” Harris and Stevens describe PSDs as occupying only a small portion of spine surface and suggest that larger PSDs contain more receptors. Our copy does not establish that the receptors are specifically AMPA receptors or give the stated 0.1–0.5 μm PSD diameter. (LLM, conf=0.79)
- Partly supportedcites [19] Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998). sourceExperimental — accuracy not yet measured
The paper’s Figure 9 caption shows AMPA-receptor labeling at synaptic junctions on spines, supporting the localization invoked to explain the citing authors’ own glutamate-sensitivity observations. It also shows labeling in the spine apparatus and extrasynaptic membrane, and the passages do not establish the stated PSD diameter of 0.1–0.5 μm. The asymmetric glutamate-sensitivity finding is attributed to the citing paper’s figures, not to this source. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [20] Takumi, Y., Ramirez-Leon, V., Laake, P., Rinvik, E. & Ottersen, O.P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat. Neurosci. 2, 618–624 (1999). source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Partly supported
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
“The relationship between spine geometry and expression of functional AMPA receptors demonstrated here provides substantial support to the hypothesis that neuronal fine structures have functional correlates in the brain13, 18, 21.”
What the sources say
- Supportedcites [13] 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). source
In “Serial electron microscopy,” the paper reports that spine-head dimensions correlate with postsynaptic density area and presynaptic vesicle number, and interprets this as evidence that spine-head dimensions reflect synaptic efficacy. That supports the cited hypothesis that neuronal fine structure has functional correlates. The AMPA-receptor relationship is described as demonstrated in the citing paper itself, not attributed to this source; page numbers are not shown for the decisive passages. (LLM, conf=0.90)
- Not matchedcites [18] Cajal, R. y. Histologie du Systeme Nerveux de l'Homme et des Vertebres (Maloine, Paris, 1911).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [21] Segal, M., Korkotian, E. & Murphy, D. D. Dendritic spine formation and pruning: common cellular mechanisms? Trends Neurosci. 23, 53–57 (2000). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
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
“Under physiological conditions, MNI-glutamate was stable for 24 hours, and did not activate any current at a concentration of 10 mM.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“This uncaging regime produced little or no photodamage29, as shown by the stability of the amplitudes of the 2pEPSCs over 1 min (Fig. 1h).”
What the sources say
- Not checked — no full text of the sourcecites [29] Hopt, A. & Neher, E. Highly nonlinear photodamage in two-photon fluorescence microscopy. Biophys. J. 80, 2029–2036 (2001). source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Under physiological conditions, MNI-glutamate was stable for 24 hours, and did not activate any current at a concentration of 10 mM.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The time course of 2pEPSC is well-predicted (smooth line in Fig. 1c) from rapid photolysis (10μs) of MNI-glutamate within a focal volume of two-photon excitation with lateral and axial full-width-at-half-maximal (FWHM) diameter of 0.29 and 0.89μm, respectively (black lines in Fig. f and g; see Methods).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“The spatial resolution of glutamate receptor activation was inferred from a small, isolated, glutamate-sensitive region of a dendrite (Fig. 2d), yielding lateral and axial FWHM diameters of 0.45 and 1.1μm, respectively (green lines in Fig. 1f and g).”
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 13
- Probably not a substantial claim. 16
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Given that each spine receives only one synaptic input13, our data indicate the highest possible degree of freedom is available in synaptic connections in the dendrites, which has been assumed in the learning models of most neural network theories17.”
What the sources say
- Partly supportedcites [13] 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
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [17] Arbib, M. A. The Handbook of Brain Theory and Neural Networks (MIT Press, Cambridge, Massachusetts, 1995). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
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
“These data are consistent with the correlation between AMPA receptor immunoreactivity and the size of PSD19, 20, because the size of PSD is nearly proportional to the spine-head volume13.”
What the sources say
- Supportedcites [19] Nusser, Z. et al. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21, 545–559 (1998). source
Figure 4B and 4D report significant positive correlations between synapse size and AMPA-receptor immunoparticle content in Schaffer collateral and mossy fiber synapses. The separate claim about spine-head volume is attached to citation 13, not to this source. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [20] Takumi, Y., Ramirez-Leon, V., Laake, P., Rinvik, E. & Ottersen, O.P. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat. Neurosci. 2, 618–624 (1999). source
- Supportedcites [13] 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). source
The Serial electron microscopy section reports that PSD area is positively correlated with spine volume, much more strongly with spine-head volume than with spine-neck volume. The Discussion describes spine-head dimensions as proportional to PSD area. The AMPA receptor immunoreactivity correlation is attached to other citations, not this source. (LLM, conf=0.93)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Supported
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
“Moreover, it did not affect either the amplitude (Fig. 1b) or the time course (Fig. 1b, inset) of miniature excitatory postsynaptic currents (mEPSCs), indicating that it does not exert an antagonistic effect at AMPA receptors.”
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“We developed a methoxy derivative of nitroindolino-glutamate, MNI-glutamate (Fig. 1a), that possesses a two-photon cross section (0.06 GM; 1 GM = 10−50 cm4s/photon2) sufficiently large for biological application (see Methods).”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“Thin spines exhibited little (Fig. 4a and b) or slight glutamate sensitivity (Fig. 4c–e), and thick mushroom spines displayed large sensitivity to uncaged glutamate (Fig. 4f–j).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“The spatial resolution of AMPA-receptor mapping was slightly reduced compared with cultured neurons, 0.6μm laterally and 1.4μm axially, because of the smaller numerical aperture (NA) of the lens used (0.9).”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In young animals (7 to 9 days old), dendrites were decorated only sparsely with spines34, and most of the dendritic shaft was devoid of glutamate sensitivity (Fig. 4l), although marked expression of functional AMPA receptors was already apparent in mushroom spines present (Fig. 4l).”
What the sources say
- Not checked — no full text of the sourcecites [34] Durand, G. M., Kovalchuk, Y. & Konnerth, A. Long-term potentiation and functional synapse induction in developing hippocampus. Nature 381, 71–75 (1996). source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“The glutamate sensitivity of each PSD (as defined by the maximum glutamate sensitivity of a spine) was significantly correlated with the volume of the spine head (Fig. 5a); the correlation coefficient (r) was 0.69–0.90 (0.80 ± 0.07; n = 9) within one dendrite (0.89, Fig. 5b) and 0.77 for average of 9 dendrites (Fig. 5c).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The maximal glutamate sensitivity of a spine reflects the number of functional AMPA receptors in that spine.
In the paper
“The two-photon action cross section of MNI-glutamate was obtained as 0.06 GM at 730 nm, using azid-1 as a standard compound with a known action cross section of 1.0 GM at 730 nm48.”
What the sources say
- Not checked — no full text of the sourcecites [48] Brown, E. B., Shear, J. B., Adams, S. R., Tsien, R. Y. & Webb, W. W. Photolysis of caged calcium in femtoliter volumes using two-photon excitation. Biophys. J. 76, 489–499 (1999). source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“The time course of 2pEPSC (Fig. 3bA–C) is similar to spontaneous mEPSCs (Fig. 3bE).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“We also detected slow NMDA-mediated currents when Mg2+ was removed from the extracellular solution; the distribution of these currents was less heterogeneous than that of AMPA receptors, and most spines expressed NMDA receptors (data not shown).”
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“For instance, the peak glutamate concentration at the center of irradiation reaches 0.6 mM focally, at a laser power of 7 mW, MNI-glutamate concentration (CMNI) of 8 mM, the duration of irradiation (td) of 50 μs.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“and those larger than 20 μs predict greater loss of spatial resolution than actually obtained (Fig. 1f)”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The evoked currents had a small coefficient of variation (CV) of 0.08, consistent with the post-synaptic action of glutamate23.”
What the sources say
- Not checked — no full text of the sourcecites [23] Liu, G., Choi, S. & Tsien, R. W. Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices. Neuron 22, 395–409 (1999). source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“In the condition listed above, the peak opening probability was 0.15 and 0.2 for 2pEPSC and mEPSC, respectively.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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 might result from less effective transport of AMPA receptors into thinner spines with smaller volume-to-surface ratios.”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“The animal experiments were approved by the animal experiment committee of the National Institute for Physiological Sciences, Japan.”
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In the paper
“The spine-head volume was estimated by total fluorescence of the spine head in the fluorescence images, which was calibrated using the large spine head whose volume (0.087μm3, spine A in Fig. 3f) could be directly estimated by a FWHM diameter.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
“The error due to the sampling intervals was estimated as 0.1 (CV), given the spatial resolution of glutamate mapping as 0.6μm laterally and 1.4μm axially.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Such a weak correlation may be due to the presence of several spines with long length and small spine-head volume (Fig. 5e).”
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“These data conform with the development of AMPA receptor immunoreactivity in CA1 pyramidal neurons35.”
What the sources say
- Not checked — no full text of the sourcecites [35] Petralia, R. S. et al. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat. Neurosci. 2, 31–36 (1999). source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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 point spread function of the focal volume of two-photon excitation were estimated using a 0.1μm fluorescent beads as 0.29 μm (FWHM) laterally and 0.89 μm axially for the inverted microscope (NA, 1.2), and 0.39μm laterally and 1.28μm axially for the upright microscope (NA, 0.9).”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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
“The access resistance was 70% compensated for the experiments shown in Fig. 1c–g but not for others.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. 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
“We estimated the CV of the two-photon excitation to be less than 0.03, by measuring the two-photon excited fluorescence of a polar tracer, Alexa Fluor 594 hydrizide (0.2 mM, Molecular Probes, Eugene, Oregon), applied to slice preparations similarly to MNI-glutamate.”
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“Using two-photon excitation of a caged-glutamate compound, we showed that the expression of functional AMPA receptors among spines shows a large range (CV, 0.5), varying from the minimal (silent) to those bearing more than 140 AMPA channels, and has a strong correlation with spine-head volume.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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 powerful approach thus allows the optical stimulation of dendritic processes in brain slices at the level of the individual synapse.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
The maximal glutamate sensitivity of a spine reflects the number of functional AMPA receptors in that spine.
“The glutamate sensitivity of each PSD (as defined by the maximum glutamate sensitivity of a spine) was significantly correlated with the volume of the spine head (Fig. 5a);”
The paper relies on this without support.
In the presence of 0.1 mM cyclothiazide, the opening probability of AMPA receptors is greater than 0.5.
“We added the desensitization inhibitor cyclothiazide (0.1 mM, CTZ) to increase the opening probability of AMPA receptors to greater than 0.5.”
The paper relies on this without support.
The largest mEPSC (~19 pA) likely occurred in the mushroom spines with the largest number of AMPA receptors (N = 147, i = 0.48 pA).
“because the opening probability of the AMPA receptors was estimated as 0.27, given that the largest mEPSC was ~19 pA (n = 222) in our experiments, and that such mEPSC likely occurred in the mushroom spines with largest number of AMPA receptors (N = 147, i = 0.48 pA).”
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Spine head size is positively correlated with mEPSC amplitude [65], and the functional loss of NMDA receptors in DG granule cells has been associated with impairments in pattern separation [8].”
From Arf4 Determines Dentate Gyrus-Mediated Pattern Separation by Regulating Dendritic Spine Development (2012) · cites this paper as [65]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Given that large spines have been shown to express AMPA receptors abundantly8”
From Structural basis of long-term potentiation in single dendritic spines (2004) · cites this paper as [8]
In the citing paper
“Two-photon uncaging allows the release of glutamate within a small focal volume8, so that activation of glutamate receptors is limited to a region within ca. 1 μm of the uncaging beam.”
From Structural basis of long-term potentiation in single dendritic spines (2004) · cites this paper as [8]
In the citing paper
“which express a small number of AMPA receptors8.”
From Structural basis of long-term potentiation in single dendritic spines (2004) · cites this paper as [8]
In the citing paper
“Amplitudes of AMPA currents were 1–25 pA, (measured with perforated patch-clamp experiments), which were within the range of miniature excitatory postsynaptic currents8.”
From Structural basis of long-term potentiation in single dendritic spines (2004) · cites this paper as [8]
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“In general, the size of the spine head positively correlates with the amount of AMPA-receptors and also influences Ca 2 dynamics (Matsuzaki et al., 2001), thus possibly indicating the strength of the synapse (Hayashi and Majewska, 2005).”
BackgroundGlutamate receptor dynamics in dendritic microdomains.
Newpher, T. M., & Ehlers, M. D. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.030 · Cited by 356
“This method has been used to measure the strength of responses along dendrites, which ultimately reveals the location and density of functional glutamate receptors (Pettit et al., 1997; Pettit and Augustine, 2000; Matsuzaki et al., 2001; Smith et al., 2003).”
Hung, A. Y., Futai, K., Sala, C., Valtschanoff, J. G., Ryu, J., Woodworth, M. A., Kidd, F. L., Sung, C. C., Miyakawa, T., Bear, M. F., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3032-07.2008 · Cited by 350
“Dendritic spine size is positively correlated with synaptic strength, size of the PSD and presynaptic active zone, and the number of docked vesicles per active zone (Harris and Stevens, 1989; Matsuzaki et al., 2001).”
BackgroundThe Dendritic Branch Is the Preferred Integrative Unit for Protein Synthesis-Dependent LTP
Govindarajan, A., Israely, I., Huang, S.-Y., & Tonegawa, S. (2011) · Neuron · doi:10.1016/j.neuron.2010.12.008 · Cited by 349
Synaptic Integration Gradients in Single Cortical Pyramidal Cell Dendrites
Branco, T., & Häusser, M. (2011) · Neuron · doi:10.1016/j.neuron.2011.02.006 · Cited by 361
“recordings from layer 2/3 pyramidal cells in the somatosensory and visual cortex to monitor somatic voltage changes, and activated an increasing number of synapses with two-photon glutamate uncaging (Gasparini and Magee, 2006; Losonczy and Magee, 2006; Matsuzaki et al., 2001).”
Transcellular Nanoalignment of Synaptic Function
Biederer, T., Kaeser, P. S., & Blanpied, T. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.10.006 · Cited by 352
“CA3-CA1 synapses contain an average of near 100 AMPARs (Matsuzaki et al., 2001; Nusser et al., 1998; Takumi et al., 1999).”
Ca2+ signaling in dendritic spines
Sabatini, B. L., Maravall, M., & Svoboda, K. (2001) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00218-x · Cited by 359
“TPPR on single spines can produce postsynaptic currents with amplitudes and time-courses that mimic unitary synaptic currents (12, 63).”
Molecular mechanisms of dendritic spine development and remodeling
Ethell, I. M., & Pasquale, E. B. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.02.003 · Cited by 367
Li, C., Brake, W. G., Romeo, R. D., Dunlop, J. C., Gordon, M., Buzescu, R., Magariños, A. M., Allen, P. B., Greengard, P., Luine, V. N., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307313101 · Cited by 355
ORGANELLES AND TRAFFICKING MACHINERY FOR POSTSYNAPTIC PLASTICITY
Kennedy, M. J., & Ehlers, M. D. (2006) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.29.051605.112808 · Cited by 346
“Spine size correlates with AMPA receptor abundance and synaptic strength (Matsuzaki et al. 2001,Takumi et al. 1999).”
BackgroundLuczynski, P., Whelan, S. O., O'SULLIVAN, C. T. D., Clarke, G. A., Shanahan, F., Dinan, T. G., & Cryan, J. F. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13291 · Cited by 360
“Mushroom spines are crucial for the formation of mature, long-lasting glutamatergic synapses (Matsuzaki et al., 2001, 2004; Kasai et al., 2003; Holtmaat et al., 2005); therefore, changes in their number likely have a significant influence on the number of excitatory inputs the neurons of GF mice…”
BackgroundState-Dependent Calcium Signaling in Dendritic Spines of Striatal Medium Spiny Neurons
Carter, A. G., & Sabatini, B. L. (2004) · Neuron · doi:10.1016/j.neuron.2004.10.013 · Cited by 347
Rapid Redistribution of Synaptic PSD-95 in the Neocortex In Vivo
Gray, N. W., Weimer, R. M., Bureau, I., & Svoboda, K. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040370 · Cited by 350
Two-Photon Microscopy of Cells and Tissue
Rubart, M. (2004) · Circulation Research · doi:10.1161/01.res.0000150593.30324.42 · Cited by 344
Remote Control of Neuronal Signaling
Rogan, S. C., & Roth, B. L. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.003020 · Cited by 339
“Second, in vivo use of RASSLs (Ro1 and Rs1) has resulted in fatal baseline (in the absence of agonist) pathologic conditions in multiple tissues.”
BackgroundThe role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity
Chater, T. E., & Goda, Y. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00401 · Cited by 377
“…AMPAR subunits (GluA1– GluA4) are encoded by the genes GRIA1-GRIA4, and are assembled as dimers-of-dimers to form the hetero-tetrameric receptors (Hollmann and Heinemann, 1994; Traynelis et al., 2010), although homo-tetrameric receptors have been reported (Wenthold et al., 1996; Lu et al., 2009).”
BackgroundInfluence of glutamate and GABA transport on brain excitatory/inhibitory balance
Sears, S. M. S., & Hewett, S. J. (2021) · Experimental Biology and Medicine · doi:10.1177/1535370221989263 · Cited by 371
“Enriched at glutamatergic synapses, AMPARs mediate fast synaptic transmission and are a key determinate of the morphology of the dendritic spine.(168,169) Membrane trafficking of AMPARs into and out of the synapse also regulates synaptic strength and plasticity.”
BackgroundProtein kinase A regulates calcium permeability of NMDA receptors
Skeberdis, V. A., Chevaleyre, V., Lau, C. G., Goldberg, J. H., Pettit, D. L., Suadicani, S. O., Lin, Y., Bennett, M. V. L., Yuste, R., Castillo, P. E., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1664 · Cited by 332
Wearne, S. L., Rodriguez, A., Ehlenberger, D. B., Rocher, A. B., Henderson, S. C., & Hof, P. R. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2005.05.053 · Cited by 331
Experience-dependent structural plasticity in the cortex
Fu, M., & Zuo, Y. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.02.001 · Cited by 322
Rapid Golgi Analysis Method for Efficient and Unbiased Classification of Dendritic Spines
Risher, W. C., Ustunkaya, T., Singh Alvarado, J., & Eroglu, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107591 · Cited by 325
“receptors to sustain high levels of synaptic activity [2,5].”
BackgroundDelayed Stabilization of Dendritic Spines in Fragile X Mice
Cruz-Martin, A., Crespo, M., & Portera-Cailliau, C. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0577-10.2010 · Cited by 321
“Previous work has established a strong correlation between protrusion size and synaptic strength (Matsuzaki et al., 2001; Zito et al., 2009), and modulating synaptic strength results in changes in spine volume (Lang et al.”
BackgroundPrinciples of Long-Term Dynamics of Dendritic Spines
Yasumatsu, N., Matsuzaki, M., Miyazaki, T., Noguchi, J., & Kasai, H. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0603-08.2008 · Cited by 321
“In the dendrites of pyramidal neurons, we and others have observed a tight structure–function relationship for excitatory synaptic connections made on spiny protrusions (Matsuzaki et al., 2001; Smith et al., 2003; Xie et al., 2005; Beique et al., 2006; Asrican et al., 2007).”
BackgroundMethodInfluentialSelf-citationRescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice
de Vrij, F. M. S., Levenga, J., van der Linde, H. C., Koekkoek, S. K., De Zeeuw, C. I., Nelson, D. L., Oostra, B. A., & Willemsen, R. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.04.002 · Cited by 313
Metadata
- Authors
- Matsuzaki, M., Ellis-Davies, G. C. R., Nemoto, T., Miyashita, Y., Iino, M., & Kasai, H.
- Affiliations
- National Institute for Physiological Sciences (JP)
- The University of Tokyo (JP)
- Corresponding author
- Kasai, Haruo
- Venue
- Nature Neuroscience
- Published
- 2001-10-22
- Volume
- 4
- Issue
- 11
- Pages
- 1086-1092
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4229049
- OpenAlex
- W1798313689
- Semantic Scholar
- 0791a25208e00590f1e05aade330dddd88a94dc4
- Cited by
- 1,563
- References
- 53
- Citations by year
- 2026: 30 · 2025: 49 · 2024: 45 · 2023: 70 · 2022: 64 · 2021: 90 · 2020: 71 · 2019: 76 · 2018: 75 · 2017: 65 · 2016: 78 · 2015: 84 · 2014: 75 · 2013: 75 · 2012: 81
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM 53395, R01 GM053395)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- dendritic spines, AMPA receptors, spine geometry, mushroom spines, filopodia, silent synapses, CA1 pyramidal neurons, hippocampus, glutamate uncaging, excitatory synapses, synaptic plasticity
- MeSH terms
- Animals, Cells, Cultured, Dendrites, Electrophysiology, Glutamates, Hippocampus, Indoles, Mathematics, Microscopy, Fluorescence, Photolysis, Molecular Structure, Rats, Wistar, Pyramidal Cells, Receptors, AMPA, Patch-Clamp Techniques, Glutamic Acid, Excitatory Postsynaptic Potentials, Cell Surface Extensions, Rats, In Vitro Techniques
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