The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index; 10 of the 26 sources its claims cite were checked for support.
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Open accessAbstract
To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.
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TL;DR
This study shows that astrocytes actively engulf and eliminate synapses in the developing and adult mouse CNS, using the phagocytic receptors MEGF10 and MERTK. Loss of both pathways impairs retinogeniculate refinement and leaves excess functional synapses.
Key findings
- Astrocytes engulfed synaptosomes in vitro and synaptic material in vivo; engulfed debris co-localized with the lysosomal marker LAMP2, and super-resolution (array tomography) and serial block-face EM showed intact pre- and postsynaptic elements inside astrocytes.
- In vivo phagocytic index was reduced by about 45% in Megf10−/− and 58% in Mertk−/− dLGN astrocytes, and by roughly 85% in Megf10−/−;Mertk−/− astrocytes, suggesting the two receptors act in parallel.
- Megf10−/−;Mertk−/− mice showed incomplete eye-specific segregation at P30 and, at P15–18, no fully refined dLGN neurons (versus 91% of wild-type neurons receiving 1–4 inputs); single-fiber responses were weaker, with each fiber contributing 16.3 ± 0.03% of total innervation versus 40.6 ± 0.07% in wild type.
- Blocking retinal waves with epibatidine reduced astrocyte engulfment, and monocular epibatidine caused preferential engulfment of the weaker projection that was diminished in Megf10−/− and Mertk−/− backgrounds. In adult (1- and 4-month) somatosensory cortex, astrocytes engulfed both excitatory and inhibitory synapses.
Methods
- In vitro engulfment assays using immunopanned astrocytes and microglia from wild-type, Megf10−/−, and Mertk−/− cortex incubated with tdTomato- or pHrodo-conjugated synaptosomes, quantified by imaging and FACS.
- In vivo retinogeniculate assays in Aldh1l1-EGFP and CX3CR1-EGFP mice with intraocular CTB labeling, confocal imaging, a custom MATLAB algorithm to isolate engulfed debris, plus array tomography and serial block-face EM.
- Electrophysiology on acute P15–18 slices (step-counting and minimal-stimulation fiber-fraction methods), eye-segregation analysis at P29–P30, epibatidine injections, and retinal wave recordings; statistics by ANOVA with Dunnett's tests, t-tests, and Kolmogorov–Smirnov tests.
Limitations
- The paper notes that MERTK is expressed by microglia as well as astrocytes, and that Mertk−/− microglia showed a transient increase in engulfed debris at P4–P5, so microglia may partly compensate for reduced astrocyte phagocytosis; it also states that astrocyte engulfment is independent of C1q (data not shown).
- The authors raise unresolved questions about how neural activity controls phagocytosis, whether astrocytes and microglia target different synapse types or circuits, and how astrocytes select which synapses to engulf.
- Evident from the text: several key mechanistic claims (e.g., C1q independence, persistence of MEGF10/MERTK mRNA in adult astrocytes) rest on unpublished data or are not shown, and the relative astrocyte-versus-microglia contribution is inferred from per-cell-volume and cell-number comparisons rather than direct functional competition experiments.
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Claims the paper makes
10 of 26 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Using Array Tomography (AT), a super-resolution imaging technique visualizing synaptic protein expression with sub-100nm volumetric resolution20, we found that astrocytes engulfed much of the CTB-labeled debris as well as synaptic material immunolabeled for both presynaptic (Bassoon) and postsynaptic (PSD-95 and GluR1) proteins (Extended Data Fig. 5).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
What the sources say
- Partly supportedcites [20] Wang, G. & Smith, S. J. Sub-diffraction limit localization of proteins in volumetric space using Bayesian restoration of fluorescence images from ultrathin specimens. PLOS Comput. Biol. 8, e1002671 (2012) sourceExperimental — accuracy not yet measured
Citation 20 is attached to the description of array tomography, not to the citing authors’ finding that astrocytes engulf synaptic material. The Introduction identifies array tomography as a technique for immunolabeling proteins in ultrathin sections, but specifies 50–100 nm axial resolution while noting that lateral resolution remains diffraction-limited at approximately 200 nm. It therefore does not establish sub-100 nm resolution throughout the volume. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“we previously performed gene expression analysis on purified mouse astrocytes and found that they are enriched in genes for phagocytic pathways2, including two phagocytic receptors, Megf10 and Mertk.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Abstract
What the sources say
- Supportedcites [2] Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008) source
The “Analysis of genes expressed by astrocytes” section reports enriched phagocytic pathways in mouse astrocytes, identifies Megf10 as an enriched pathway gene, and identifies Mertk as a phagocytic receptor expressed by astrocytes. The “Several evolutionarily conserved phagocytic pathways are highly enriched in astrocytes” section also describes the Mertk/Axl pathway as highly enriched in astrocytes in vivo. Page numbers were not supplied in the passages. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Recently, it has been shown that microglial cells also mediate synapse elimination in the developing retinogeniculate system22.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
What the sources say
- Supportedcites [22] Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012) source
The Discussion states that microglia mediate synaptic pruning in the developing brain and engulf retinal ganglion cell presynaptic terminals in the postnatal dLGN. It also specifically implicates microglia in pruning transient retinogeniculate synapses, matching the cited claim. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Interestingly, we found that more excitatory synapses were engulfed by 1-month than 4-month old cortical astrocytes (Fig. 6d), likely due to a higher rate of developmental synapse pruning of excitatory projections in the younger brains30.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Continuous synapse elimination by astrocytes in the adult brains
What the sources say
- Supportedcites [30] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011) source
The citation supports the proposed explanation, not the citing authors’ own Fig. 6d finding about cortical astrocytes. The paper’s Abstract says synaptic turnover is highest during synaptic maturation, and its main text reports that microglia engulf and eliminate synapses during development. It does not itself compare engulfment by 1- and 4-month-old astrocytes. (LLM, conf=0.86)
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Astrocytes thus share with microglia, the ability to actively engulf and eliminate synapses in response to neural activity, but synapse engulfment by astrocytes is independent of complement protein C1q31 (data not shown), and use distinct phagocytic pathways from microglia.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Concluding Remarks
What the sources say
- Could not verifycites [31] Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007) sourceExperimental — accuracy not yet measured
The Introduction and Discussion describe astrocyte-induced C1q expression and complement-dependent synapse elimination in the developing retinogeniculate pathway. They do not address whether astrocytes themselves engulf synapses or whether that engulfment is independent of C1q; searches for astrocyte engulfment and phagocytosis did not resolve that point. (LLM, conf=0.76)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Could not verify
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, putative synapses that contain both CTB-positive presynaptic, and PSD-95 (Fig. 2e)- or GluR1 (Fig. 2f)-positive postsynaptic proteins were frequently found adjoined together inside of astrocytes, indicating that entire synapses had been engulfed.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
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
“Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections and retain excess functional synapses.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Abstract
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
“Importantly, we found a significant amount of CTB-labeled neural debris inside of EGFP-expressing astrocytes (Fig. 2c).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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
“As a result, the total amount of engulfed CTB-labeled debris in a given imaging field was much greater in astrocytes (Extended Data Fig. 6d) during P3-P9, suggesting that the total amount of synaptic pruning by astrocytes could exceed that by microglia in the developing LGN.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
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
“However, we found that astrocytes significantly outnumber microglia by 10-, 7-, 6- and 4-folds, at P5, P6, P7 and P9, respectively (Extended Data Fig. 6a, b).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 4
- It may state two separate claims as one. 10
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Synapses in the adult brain, especially dendritic spines, are dynamic structures that turn over rapidly during activity-dependent synaptic plasticity induced by learning and memory27-29.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Continuous synapse elimination by astrocytes in the adult brains
What the sources say
- Partly supportedcites [27] Xu, T. et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462, 915–919 (2009) sourceExperimental — accuracy not yet measured
The Abstract reports rapid dendritic spine formation during motor-skill learning, including novel skill learning in adult mice, followed by elimination of pre-existing spines. It studies pyramidal neurons in the mouse motor cortex, so it does not establish rapid turnover of synapses throughout the adult brain; spine elimination is described as gradual. (LLM, conf=0.82)
- Partly supportedcites [28] Yang, G., Pan, F. & Gan, W. B. Stably maintained dendritic spines are associated with lifelong memories. Nature 462, 920–924 (2009) sourceExperimental — accuracy not yet measured
The paper’s introductory discussion says synaptic connections can change rapidly after learning, supporting the claim that they are dynamic. But it also describes adult dendritic spines as remarkably stable, and the Abstract says learning-related spine formation and elimination occur through a protracted process. It does not support the claim that adult spines generally turn over rapidly. (LLM, conf=0.88)
- Partly supportedcites [29] Roberts, T. F., Tschida, K. A., Klein, M. E. & Mooney, R. Rapid spine stabilization and synaptic enhancement at the onset of behavioural learning. Nature 463, 948–952 (2010) sourceExperimental — accuracy not yet measured
The paper reports dendritic-spine turnover in both juvenile and adult zebra finches (Abstract, page unavailable), supporting the claim that spines are dynamic. But its learning experiments concern juveniles: higher turnover preceded successful song learning, while tutoring rapidly decreased turnover. It does not establish rapid turnover during learning-induced plasticity in the adult brain. (LLM, conf=0.89)
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.
- 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
“Previous work has shown that injecting epibatidine binocularly blocks eye-specific segregation in dLGN, whereas injecting epibatidine monocularly preserves eye-specific segregation, inducing the affected weaker projections to lose their territory preferentially.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Retinal activity promotes astrocyte-mediated synapse elimination
What the sources say
- Not checked — no full text of the sourcecites [17] Penn, A. A., Riquelme, P. A., Feller, M. B. & Shatz, C. J. Competition in retinogeniculate patterning driven by spontaneous activity. Science 279, 2108–2112 (1998) source
- Not checked — no full text of the sourcecites [25] Stellwagen, D. & Shatz, C. J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002) source
- Supportedcites [26] Huberman, A. D., Stellwagen, D. & Chapman, B. Decoupling eye-specific segregation from lamination in the lateral geniculate nucleus. J. Neurosci. 22, 9419–9429 (2002) source
The Results section, “Activity blockade prevents segregation of eye-specific inputs to the LGN” (page unavailable), reports that immediately after binocular epibatidine treatment from P1 to P10, inputs from the two eyes still overlapped across approximately 50% of the ferret LGN, unlike segregated controls. The claim is supported for segregation during treatment; the paper separately reports that segregation occurred after treatment ended. (LLM, conf=0.94)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Previous work has shown that injecting epibatidine binocularly blocks eye-specific segregation in dLGN, whereas injecting epibatidine monocularly preserves eye-specific segregation, inducing the affected weaker projections to lose their territory preferentially.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Retinal activity promotes astrocyte-mediated synapse elimination
What the sources say
- Not checked — no full text of the sourcecites [17] Penn, A. A., Riquelme, P. A., Feller, M. B. & Shatz, C. J. Competition in retinogeniculate patterning driven by spontaneous activity. Science 279, 2108–2112 (1998) source
- Not checked — no full text of the sourcecites [25] Stellwagen, D. & Shatz, C. J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002) source
- Partly supportedcites [26] Huberman, A. D., Stellwagen, D. & Chapman, B. Decoupling eye-specific segregation from lamination in the lateral geniculate nucleus. J. Neurosci. 22, 9419–9429 (2002) sourceExperimental — accuracy not yet measured
The Results section reports that binocular epibatidine treatment prevented eye-specific segregation in ferrets at P10. The copy describes territory gained by an active eye at the expense of an inactive eye only in a passage indexed as the Abstract; the non-abstract passages do not establish that monocular epibatidine preserves segregation or preferentially reduces the treated projection. (LLM, conf=0.82)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The engulfment ability of astrocytes was highly dependent on the presence of secreted factors, since addition of astrocyte-conditioned media (ACM), 5% serum or Protein S (a bridging molecule that bridges phosphatidylserine-MERTK interaction)9 greatly increased the amount of synaptosomes engulfed by astrocytes whereas addition of fresh media (unconditioned astrocyte growth media, AGM) did not (Fig.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
What the sources say
- Not checked — no full text of the sourcecites [9] Prasad, D. et al. TAM receptor function in the retinal pigment epithelium. Mol. Cell. Neurosci. 33, 96–108 (2006) 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
“Functional MEGF10 and MERTK proteins were absent in the Megf10—/— and Mertk—/— postnatal brains (Fig. 1f), confirming the specificity of antibodies.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Localization of MEGF10 and MERTK to astrocytes
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
“MERTK protein expression was highly localized to developing astrocytes in the P5 dLGN (Fig. 1c), as well as to microglia and endothelial cells (Extended Data Fig. 1).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Localization of MEGF10 and MERTK to astrocytes
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
“We also compared the phagocytic capacity of enriched microglial population using FACS analysis, and found that unlike Megf10—/— microglia (Extended Data Fig. 3b, f), Mertk—/— microglia exhibited a 25% reduction in the relative engulfment ability (Extended Data Fig. 3d, f).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ 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
“Both MEGF10 and MERTK mRNA expression and immunoreactivity persisted in adult astrocytes (data not shown and Extended Data Fig. 2).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Localization of MEGF10 and MERTK to astrocytes
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
“As we had observed in vitro, we found that astrocytes in vivo in the Megf10—/— and Mertk—/— dLGNs displayed a 45 and 58 % reduction, respectively, in their relative engulfment ability compared to wild type (Fig. 3e).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
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
“In contrast, Megf10—/—; Mertk—/— neurons received a larger number of inputs, as shown by a rightward shift in the distribution of the number of inputs (Fig. 4c).”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Neural circuit pruning and refinement by astrocytes
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
“As a result, wild type neurons fell into either the refined or resolving category (Fig. 4d) whereas we found no fully refined Megf10—/—; Mertk—/— neurons at this age, and the majority of Megf10—/—; Mertk—/— neurons remained multiply innervated (Fig. 4d), indicating a significant deficit in synapse elimination.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Neural circuit pruning and refinement by astrocytes
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
“FACS analysis with enriched microglial cells showed two distinct cell populations with low and strong pHrodo intensity.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Methods > In vitro engulfment assay with microglia
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 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
“Thus MEGF10 and MERTK are each required for astrocyte-mediated phagocytosis.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Astrocytes phagocytose synapses in vitro and in vivo
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“This method preserves the optic tract and dLGN, and generally only one slice is obtained per animal.”
§ Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways > Methods > Electrophysiology
What the sources say
- Not checked — no full text of the sourcecites [18] Hooks, B. M. & Chen, C. Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse. Neuron 52, 281–291 (2006) source
- Not checked — no full text of the sourcecites [23] Chen, C. & Regehr, W. G. Developmental remodeling of the retinogeniculate synapse. Neuron 28, 955–966 (2000) source
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.
The paper relies on this without support.
The mechanisms of developmental synapse remodeling other than those mediated by microglia are unknown.
“Recently microglial cells have been shown to be responsible for a portion of synaptic remodeling, but the remaining mechanisms remain mysterious.”
The paper relies on this without support.
One astrocyte ensheaths thousands of synapses.
“Since astrocytes highly express phagocytic receptors as well as all their other interacting proteins listed above2, and one astrocyte has been shown to ensheath thousands of synapses, we hypothesized that astrocytes mediate synapse elimination within the developing and adult CNS through the MEGF10 and/or MERTK phagocytic pathways.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition to the tripartite synapse, the more recent concepts of the four-part extracellular matrix and the microglial five-part synapse 220 also support the idea that glial dysfunction plays key roles in the early pathological features common to psychiatric disorders. 221 , 222”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [221]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As the most numerous cell type in the mammalian brain, astrocytes support neurite outgrowth, neuronal survival, synapse formation and synaptic pruning, all of which are vital during brain development (Chung et al., 2013; Clarke and Barres, 2013).”
From Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk (2022) · cites this paper as Chung et al., 2013
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This phagocytic deficit corresponded with a 90% decrease in Mertk and 60% decrease in Megf10 mRNA, phagocytic receptors we have previously found mediate synaptic phagocytosis3 (Fig. 3f).”
From Neurotoxic reactive astrocytes are induced by activated microglia (2017) · cites this paper as [3]
In the citing paper
“ApoE isoforms differentially affect this process, with ApoE4 limiting the ability of astrocytes to prune synapses [76, 77].”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [76]
In the citing paper
“and by eliminating excess synapses by phagocytosis using the receptors Mertk and Megf10 and indirectly by inducing expression of complement cascade components in neurons (Bialas and Stevens, 2013; Chung et al., 2013; Stevens et al., 2007).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Chung et al., 2013
In the citing paper
“Similar to studies in murine KO models, our data indicates that MERTK plays a minor role in human microglia-mediated synaptic pruning (Chung et al., 2013), whereas C1q/CR3 is integral for microglia-mediated synaptic pruning in humans.”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Chung et al., 2013
In the citing paper
“Astrocytes also participate in circuit refinement by synaptic engulfment of both inhibitory and excitatory synapses through MEGF10 and MERTK pathways during development and in adulthood (Chung et al., 2013) (Figure 2B).”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Chung et al., 2013
In the citing paper
“In general, MERTK plays a key role in a variety of phagocytic events, such as microglial phagocytosis to mediate synaptic pruning (Chung et al., 2013), macrophage phagocytosis to remove apoptotic immune cells (Scott et al., 2001), and phagocytosis of apoptotic germ cells and the residual body from maturing sperm by Sertoli cells in the testes (Breucker et al., 1985).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Chung et al., 2013
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.
MERTK localization is attributed to the MEGF10 panel
MinorThe later statement cites Fig. 1a for MERTK localization, whereas the paper identifies Fig. 1a as showing MEGF10 and Fig. 1c as showing MERTK.
“MERTK protein is localized to astrocytes as well as to microglia (Fig. 1a and Extended Data Fig. 1).”
“We found that MEGF10 protein was localized to developing astrocytes visualized by Aldh1l1-EGFP transgene expression2 in the postnatal day 5 (P5) dorsal lateral geniculate nucleus (dLGN) (Fig. 1a).”
Citations
Cites
Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
Paolicelli, R. C., Bolasco, G., Pagani, F., Maggi, L., Scianni, M., Panzanelli, P., Giustetto, M., Ferreira, T. A., Guiducci, E., Dumas, L., et al. (2011) · Science · doi:10.1126/science.1202529 · Cited by 4,244 · cited 1×
“6d), likely due to a higher rate of developmental synapse pruning of excitatory projections in the younger brains 30 .”
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089
Self-citationThe Classical Complement Cascade Mediates CNS Synapse Elimination
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.036 · Cited by 3,313
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“Although microglia are known to play a role in the pruning of synapses during the developmental period of eye-specific segregation at postnatal day 5, it was suggested that, given the amount of consumed neuronal material, the dominant phagocytes at that stage were astrocytes (Chung et al., 2013).”
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Microglia control glutamatergic synapses in the adult mouse hippocampus
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“…a consequence of the decreased expression of genes encoding for Mertk and/or Megf10, phagocytic receptors that mediate the binding and/or engulfment recognition of target synapses or cells (Chung et al., 2013; Iram et al., 2016; Scheib, Sullivan, & Carter, 2012; Tremblay, Cookson, & Civiero, 2019).”
BackgroundInfluentialAstrocyte-to-neuron intercellular prion transfer is mediated by cell-cell contact
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BackgroundGlial Control of Synapse Number in Healthy and Diseased Brain
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Metadata
- Authors
- Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., Smith, S. J., & Barres, B. A.
- Affiliations
- Stanford Medicine (US)
- University of Michigan (US)
- University of California, Santa Cruz (US)
- Agency for Science, Technology and Research (SG)
- Boston Children's Hospital (US)
- Corresponding author
- Chung, Won-Suk
- ORCID
- Venue
- Nature
- Published
- 2013-11-24
- Volume
- 504
- Issue
- 7480
- Pages
- 394-400
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3969024
- OpenAlex
- W2125236750
- Cited by
- 1,377
- References
- 40
- Citations by year
- 2026: 108 · 2025: 143 · 2024: 133 · 2023: 131 · 2022: 126 · 2021: 146 · 2020: 125 · 2019: 90 · 2018: 91 · 2017: 93 · 2016: 73 · 2015: 62 · 2014: 55 · 2013: 1
- FWCI
- 31.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Mental Health (T32MH020016)
- National Institute of Neurological Disorders and Stroke (NS069375, R01NS075252, P30NS069375, R21NS072556)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- astrocytes, synaptic pruning, synaptic engulfment, MEGF10, MERTK, phagocytosis, neural circuit refinement, microglia, glial cells, adult brain
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Astrocytes, Brain, Learning, Membrane Proteins, Mice, Transgenic, Neural Pathways, Phagocytosis, Proto-Oncogene Proteins, Retina, Synapses, Lateral Thalamic Nuclei, Receptor Protein-Tyrosine Kinases, Mice, In Vitro Techniques
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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