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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Written from the paper’s full text.
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.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
9 of 26 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
- Findingown data
Astrocytes engulf synaptic material immunolabeled for presynaptic and postsynaptic proteins.
“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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [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) source
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)
Experimental — accuracy not yet measured
- Premisecitation
Astrocytes are enriched in genes for phagocytic pathways, including Megf10 and Mertk.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [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
- Premisecitation
Microglial cells also mediate synapse elimination in the developing retinogeniculate system.
“Recently, it has been shown that microglial cells also mediate synapse elimination in the developing retinogeniculate system22.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012) source
- Findingcitation
More excitatory synapses are engulfed by 1-month than 4-month old cortical astrocytes.
“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.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011) source
- Findingown data
Putative synapses containing both CTB-positive presynaptic and PSD-95- or GluR1-positive postsynaptic proteins are frequently found adjoined inside astrocytes.
“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.”
Quote in the paperSubstantial claim
- Findingown data
Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections.
“Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections and retain excess functional synapses.”
Quote in the paperSubstantial claim - Findingown data
A significant amount of CTB-labeled neural debris is found inside EGFP-expressing astrocytes in the P6 dLGN.
“Importantly, we found a significant amount of CTB-labeled neural debris inside of EGFP-expressing astrocytes (Fig. 2c).”
Quote in the paperSubstantial claim - Findingreasoning
The total amount of engulfed CTB-labeled debris in a given imaging field is much greater in astrocytes during P3-P9.
“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.”
Quote in the paperSubstantial claim - Findingown data
Astrocytes significantly outnumber microglia by 10-, 7-, 6- and 4-folds at P5, P6, P7 and P9, respectively.
“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).”
Quote in the paperSubstantial claim - Findingown data
Developing mice deficient in both astrocyte pathways retain excess functional synapses.
“Developing mice deficient in both astrocyte pathways fail to normally refine their retinogeniculate connections and retain excess functional synapses.”
Quote in the paperSubstantial claim - Findingown data
Spontaneous retinal waves that drive eye-specific segregation are intact in the P6 Megf10−/−;Mertk−/− retina.
“Since photoreceptors in the Mertk—/— retina show progressive degeneration starting from P259,10, we examined spontaneous retinal waves that drive eye-specific segregation and found that they were intact in the P6 Megf10—/—; Mertk—/— retina (Extended Data Fig. 8), suggesting that incomplete eye-specific segregation was not due to any retinal defects.”
Quote in the paperSubstantial claim - Findingown data
MEGF10 protein is localized to developing astrocytes in the postnatal day 5 dorsal lateral geniculate nucleus.
“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).”
Quote in the paperSubstantial claim - Findingown data
Astrocytes actively engulf CNS synapses.
“Here we report a new role for astrocytes in actively engulfing CNS synapses.”
- Also stated in: § Astrocytes phagocytose synapses in vitro and in vivo · hedged
“This data indicates that astrocytes actively engulf synapses and suggest that astrocytes are actively helping to mediate retinogeniculate refinement.”
Quote in the paperSubstantial claim - Also stated in: § Astrocytes phagocytose synapses in vitro and in vivo · hedged
- Findingown data
In the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses.
“Lastly, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses.”
- Also stated in: § Continuous synapse elimination by astrocytes in the adult brains · boosted
“These data show that engulfment of both excitatory and inhibitory synapses by astrocytes continue in the adult CNS.”
Quote in the paperSubstantial claim - Also stated in: § Continuous synapse elimination by astrocytes in the adult brains · boosted
- Findingown data
Megf10−/− and Mertk−/− astrocytes each display about 50% reduction in relative engulfment ability.
“Using image (Fig. 1h) and FACS (Extended Data Fig. 3a, c, e) analysis, we found that Megf10—/— and Mertk—/— astrocytes each displayed about 50% reduction in their relative engulfment ability.”
Quote in the paperSubstantial claim - Findingown data
The area of dLGN occupied by ipsi-lateral projections is significantly increased in Megf10−/−;Mertk−/− mice.
“Consistent with this finding, the area of dLGN occupied by ipsi-lateral projections was significantly increased in Megf10—/—; Mertk—/— mice (Fig. 3h).”
Quote in the paperSubstantial claim - Findingown data
Serial block-face scanning electron microscopy shows double membrane-bound inclusions with vesicles the same size as presynaptic vesicles completely surrounded by astrocytic cytoplasm identified by glycogen granules.
“We found many incidents showing double membrane-bound inclusions with vesicles that are the same size as the presynaptic vesicles (Fig. 2g-j) were completely surrounded by astrocytic cytoplasm identified by the presence of glycogen granules (Fig. 2j, Supplementary Video 2)21.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Peters, A., Palay, S. L., Webster, H. & d The Fine Structure of the Nervous System: the Neurons and Supporting Cells (Saunders, 1976)
- Findingown data
In Megf10−/−;Mertk−/− mice, eye-specific segregation fails to occur properly.
“We found that in Megf10—/—; Mertk—/— mice, eye-specific segregation failed to occur properly (Fig. 3f, g).”
Quote in the paperSubstantial claim - Findingown data
The highest amount of astrocyte-mediated phagocytosis occurs at the peak period of eye-specific segregation before P6.
“By measuring the phagocytic index (PI) at different time points, we found that the highest amount of astrocyte-mediated phagocytosis occurs at the peak period of eye-specific segregation before P6 (Fig. 3d), suggesting there is a critical developmental time window for synapse elimination by astrocytes.”
Quote in the paperNot a substantial claim - Findingown data
Mertk−/− microglia display a transient increase in engulfed CTB-labeled debris compared to wild type only during P4-P5.
“Unexpectedly, we found that the Mertk—/—microglia displayed a transient increase in the amount of engulfed CTB-labeled debris compared to wild type only during P4-P5 (Extended Data Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
The overlap between contra- and ipsi-lateral projections is significantly increased in Megf10−/−;Mertk−/− mice compared to wild type and single KO mice.
“The overlap between contra- and ipsi-lateral projections was significantly increased compared to wild type and single KO mice indicating incomplete segregation (Fig. 3g).”
Quote in the paperSubstantial claim - Findingown data
Only during P3-P6, microglia engulf more CTB-labeled debris than astrocytes per unit cell volume.
“Only during P3-P6, microglia engulfed more CTB-labeled debris than astrocytes per unit cell volume (Extended Data Fig. 6c).”
Quote in the paperSubstantial claim - Findingown data
Astrocytes in Megf10−/−;Mertk−/− dLGNs show about 85% further decrease in relative engulfment ability.
“Furthermore, astrocytes in the Megf10—/—; Mertk—/— dLGNs showed a further decrease in their relative engulfment ability of about 85% (Fig. 3e), suggesting that MEGF10 and MERTK work in parallel to mediate synapse elimination in developing brains.”
Quote in the paperSubstantial claim - Findingown data
Astrocytes efficiently engulf synaptosomes in vitro.
“Using purified immunopanned astrocytes15, we developed an in vitro engulfment assay, where we cultured astrocytes in the presence of synaptosomes, which are isolated nerve terminals, and found that astrocytes efficiently engulfed synaptosomes (Fig. 1d, d’, Supplementary Video 1).”
Quote in the paperSubstantial claim - Findingown data
Most CTB-labeled neural debris engulfed by astrocytes co-localizes with LAMP2.
“Most of the CTB-labeled neural debris engulfed by astrocytes co-localized with LAMP2, a specific markers for late endosome/lysosomes (Fig. 2d)19, suggesting they are in the process of active degradation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Cuervo, A. M. & Dice, J. F. A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273, 501–503 (1996) source
- Findingcitation
By P18, the majority (91%) of wild type dLGN neurons are innervated by between 1-4 inputs.
“As previously reported18,23, we found that by P18 the majority (91%) of wild type neurons were innervated by between 1-4 inputs.”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
Binocular epibatidine does not change the ratio of engulfed contra- vs. ipsi-lateral projections compared to control injections.
“When we injected epibatidine binocularly, the total amount of both engulfed contra- (CTB-594) and ipsi-lateral (CTB-647) projections by astrocytes was significantly reduced (Fig. 5a, b, d), whereas the ratio of engulfed contra- vs. ipsi-lateral projections was unchanged compared to control injections (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Monocular epibatidine significantly increases the ratio of engulfed contra- vs. ipsi-lateral projections by astrocytes, indicating preferential engulfment of weaker projections.
“Importantly, when epibatidine was injected monocularly to wild type mice, astrocytes engulfed the weaker projections preferentially (Fig. 5c, d), significantly increasing the ratio of engulfed contra- vs. ipsi-lateral projections by astrocytes (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Binocular epibatidine significantly reduces the total amount of both engulfed contra- and ipsi-lateral projections by astrocytes.
“When we injected epibatidine binocularly, the total amount of both engulfed contra- (CTB-594) and ipsi-lateral (CTB-647) projections by astrocytes was significantly reduced (Fig. 5a, b, d), whereas the ratio of engulfed contra- vs. ipsi-lateral projections was unchanged compared to control injections (Fig. 5e).”
Quote in the paperSubstantial claim - Findingown data
Preferential engulfment of weaker projections is significantly reduced in Megf10−/− and Mertk−/− background.
“This preferential engulfment of weaker projections was significantly reduced in Megf10—/— and Mertk—/— background (Fig. 5d, e).”
Quote in the paperSubstantial claim - Findingown data
Engulfed putative inhibitory synapses show about the same density within 1- and 4-month old cortical astrocytes.
“In contrast, engulfed putative inhibitory synapses showed about the same density within 1- and 4-month old cortical astrocytes (Fig. 6d).”
Quote in the paperNot a substantial claim - Findingown data
The fiber fraction is significantly reduced in Megf10−/−;Mertk−/− neurons, with each fiber contributing 16.3 ± 0.03% of total innervation compared to 40.6 ± 0.07% in wild type cells.
“We also compared the fiber fraction ratios (FF) by quantifying the contribution of each single fiber EPSC to the maximal evoked response and found that the FF was significantly reduced in Megf10—/—; Mertk—/— neurons (Fig. 4g), with each fiber contributing only 16.3 ± 0.03% of the total innervation compared to 40.6 ± 0.07% in wild type cells.”
Quote in the paperSubstantial claim - Findingown data
Both putative excitatory and inhibitory synapses are robustly engulfed by astrocytes throughout the 1- and 4-month old cortex.
“3D-max projection AT images revealed that both putative excitatory (puncta containing Bassoon and PSD-95) and inhibitory (puncta containing Gephyrin and VGAT) synapses were robustly engulfed by astrocytes throughout the 1- and 4-month old cortex (Fig. 6a-c).”
Quote in the paperSubstantial claim - Findingown data
Synapse engulfment by astrocytes is independent of complement protein C1q.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007) source
- Findingown data
The mean amplitude of AMPA and NMDA single fiber responses is significantly reduced in Megf10−/−;Mertk−/− neurons.
“We found that the mean amplitude of AMPA and NMDA single fiber responses were significantly reduced in Megf10—/—; Mertk—/— neurons (Fig. 4e) with a leftward shift in a cumulative distribution plot compared to wild type neurons (Fig. 4f).”
Quote in the paperSubstantial claim - Interpretationown data
There is a critical developmental time window for synapse elimination by astrocytes.
“By measuring the phagocytic index (PI) at different time points, we found that the highest amount of astrocyte-mediated phagocytosis occurs at the peak period of eye-specific segregation before P6 (Fig. 3d), suggesting there is a critical developmental time window for synapse elimination by astrocytes.”
Quote in the paperSubstantial claim - Interpretationown data
Incomplete eye-specific segregation in Megf10−/−;Mertk−/− mice is not due to retinal defects.
“Since photoreceptors in the Mertk—/— retina show progressive degeneration starting from P259,10, we examined spontaneous retinal waves that drive eye-specific segregation and found that they were intact in the P6 Megf10—/—; Mertk—/— retina (Extended Data Fig. 8), suggesting that incomplete eye-specific segregation was not due to any retinal defects.”
Quote in the paperSubstantial claim - Interpretationown data
MEGF10 and MERTK work in parallel to mediate synapse elimination in developing brains.
“Furthermore, astrocytes in the Megf10—/—; Mertk—/— dLGNs showed a further decrease in their relative engulfment ability of about 85% (Fig. 3e), suggesting that MEGF10 and MERTK work in parallel to mediate synapse elimination in developing brains.”
Quote in the paperSubstantial claim - Interpretationown data
MERTK is dispensable for the phagocytic function of microglia in the developing dLGN.
“Thus, our in vivo data suggests that MERTK is dispensable for the phagocytic function of microglia in the developing dLGN, and that microglia can compensate to some extent for reduced astrocyte-mediated phagocytosis of synapses.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocyte-mediated synapse elimination requires the Megf10 and Mertk phagocytic pathways.
“This process helps to mediate synapse elimination, requires the Megf10 and Mertk phagocytic pathways, and is strongly dependent on neuronal activity.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia can compensate to some extent for reduced astrocyte-mediated phagocytosis of synapses.
“Thus, our in vivo data suggests that MERTK is dispensable for the phagocytic function of microglia in the developing dLGN, and that microglia can compensate to some extent for reduced astrocyte-mediated phagocytosis of synapses.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocyte-mediated engulfment helps mediate synapse elimination.
“This process helps to mediate synapse elimination, requires the Megf10 and Mertk phagocytic pathways, and is strongly dependent on neuronal activity.”
Quote in the paperSubstantial claim - Interpretationown data
The total amount of synaptic pruning by astrocytes could exceed that by microglia in the developing LGN.
“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.”
Quote in the paperSubstantial claim - Premisecitation
Both MEGF10 and MERTK function as engulfment receptors by recognizing eat-me signals such as phosphatidylserine presented in target debris.
“Both MEGF10 and MERTK function as engulfment receptors by recognizing “eat me signals”, such as phosphatidylserine presented in target debris13,14.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Tung, T. T. et al. Phosphatidylserine recognition and induction of apoptotic cell clearance by Drosophila engulfment receptor Draper. J. Biochem. 153, 483–491 (2013) source
- cites [14] Hochreiter-Hufford, A. & Ravichandran, K. S. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb. Perspect. Biol. 5, (2013) source
- Interpretationnone given
Astrocyte-mediated synapse elimination is strongly dependent on neuronal activity.
“This process helps to mediate synapse elimination, requires the Megf10 and Mertk phagocytic pathways, and is strongly dependent on neuronal activity.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocytes use distinct phagocytic pathways from microglia.
“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.”
Quote in the paperSubstantial claim - Interpretationcitation
The phagocytic function of astrocytes is evolutionarily conserved.
“Astrocytes in Drosophila also phagocytose synapses, suggesting the phagocytic function of astrocytes is evolutionarily conserved (Ozge Tasdemir-Yilmaz and Marc Freeman, submitted).”
Quote in the paperNot a substantial claim - Premisecitation
Retinogeniculate segregation does not occur when retinal wave activity is blocked.
“Retinogeniculate segregation does not occur when retinal wave activity is blocked17,24 raising the question of whether neural activity plays a role in astrocyte-mediated synapse elimination.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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
- cites [24] Shatz, C. J. & Stryker, M. P. Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. Science 242, 87–89 (1988) source
- Interpretationown data
Engulfment of both excitatory and inhibitory synapses by astrocytes continues in the adult CNS.
“These data show that engulfment of both excitatory and inhibitory synapses by astrocytes continue in the adult CNS.”
Quote in the paperSubstantial claim - Premisecitation
Astrocytes in Drosophila also phagocytose synapses.
“Astrocytes in Drosophila also phagocytose synapses, suggesting the phagocytic function of astrocytes is evolutionarily conserved (Ozge Tasdemir-Yilmaz and Marc Freeman, submitted).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ozge Tasdemir-Yilmaz and Marc Freeman, submitted
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Astrocytes actively contribute to the activity-dependent synapse elimination that mediates neural circuit refinement in the developing CNS by phagocytosing synapses via the MEGF10 and MERTK pathways.
“Our findings demonstrate that astrocytes actively contribute to the activity-dependent synapse elimination that mediate neural circuit refinement in the developing CNS by phagocytosing synapses via the MEGF10 and MERTK pathways, and that astrocytes continue to engulf synapses in the adult CNS.”
Quote in the paperSubstantial claim - Interpretationown data
Megf10−/−;Mertk−/− neurons are innervated by a greater number of weak inputs.
“Taken together, these data indicate that these neurons are innervated by a greater number of weak inputs and demonstrate that astrocytes contribute to normal neural circuit pruning and refinement in the developing CNS by phagocytosing weak synapses through MEGF10 and MERTK pathways.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocytes contribute to normal neural circuit pruning and refinement in the developing CNS by phagocytosing weak synapses through MEGF10 and MERTK pathways.
“Taken together, these data indicate that these neurons are innervated by a greater number of weak inputs and demonstrate that astrocytes contribute to normal neural circuit pruning and refinement in the developing CNS by phagocytosing weak synapses through MEGF10 and MERTK pathways.”
Quote in the paperSubstantial claim - Interpretationown data
Activity-dependent engulfment of synapses by astrocytes plays an active role in continually remodeling synaptic architecture of the brain.
“Most importantly our findings suggest that the activity-dependent engulfment of synapses by astrocytes plays an active role in continually remodeling synaptic architecture of our brains.”
Quote in the paperSubstantial claim - Interpretationown data
Megf10−/−;Mertk−/− mice have a significant deficit in synapse elimination.
“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.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 4
- May combine two claims. 10
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSynapses in the adult brain, especially dendritic spines, are dynamic structures that turn over rapidly during activity-dependent synaptic plasticity induced by learning and memory.
“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.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [27] Xu, T. et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462, 915–919 (2009) source
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)
Experimental — accuracy not yet measured - cites [28] Yang, G., Pan, F. & Gan, W. B. Stably maintained dendritic spines are associated with lifelong memories. Nature 462, 920–924 (2009) source
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)
Experimental — accuracy not yet measured - cites [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) source
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)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationBinocular epibatidine injection blocks eye-specific segregation in dLGN.
“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.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [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
- cites [25] Stellwagen, D. & Shatz, C. J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002) source
- cites [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
May combine two claims.
PremisecitationMonocular epibatidine injection preserves eye-specific segregation and induces the affected weaker projections to lose their territory preferentially.
“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.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [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
- cites [25] Stellwagen, D. & Shatz, C. J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002) source
- cites [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 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)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataAstrocyte engulfment ability is highly dependent on secreted factors; astrocyte-conditioned media, 5% serum or Protein S greatly increase synaptosome engulfment whereas fresh media does not.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Prasad, D. et al. TAM receptor function in the retinal pigment epithelium. Mol. Cell. Neurosci. 33, 96–108 (2006) source
May combine two claims.
Findingown dataFunctional MEGF10 and MERTK proteins are absent in Megf10−/− and Mertk−/− postnatal brains.
“Functional MEGF10 and MERTK proteins were absent in the Megf10—/— and Mertk—/— postnatal brains (Fig. 1f), confirming the specificity of antibodies.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMERTK protein expression is highly localized to developing astrocytes in the P5 dLGN, as well as to microglia and endothelial cells.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMertk−/− microglia exhibit a 25% reduction in relative engulfment ability, unlike Megf10−/− microglia.
“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).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMEGF10 and MERTK mRNA expression and immunoreactivity persist in adult astrocytes.
“Both MEGF10 and MERTK mRNA expression and immunoreactivity persisted in adult astrocytes (data not shown and Extended Data Fig. 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAstrocytes in Megf10−/− and Mertk−/− dLGNs display 45% and 58% reductions, respectively, in relative engulfment ability compared to wild type.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMegf10−/−;Mertk−/− dLGN neurons receive a larger number of inputs than wild type, with a rightward shift in the distribution of the number of inputs.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNo fully refined Megf10−/−;Mertk−/− neurons are found at P15-18, and the majority remain multiply innervated.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataFACS analysis with enriched microglial cells showed two distinct cell populations with low and strong pHrodo intensity.
“FACS analysis with enriched microglial cells showed two distinct cell populations with low and strong pHrodo intensity.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataMEGF10 and MERTK are each required for astrocyte-mediated phagocytosis.
“Thus MEGF10 and MERTK are each required for astrocyte-mediated phagocytosis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe angled parasagittal brain slice preparation preserves the optic tract and dLGN.
“This method preserves the optic tract and dLGN, and generally only one slice is obtained per animal.”
Quote in the paperNot a substantial claim0 of 2 sources checked
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 concepts of the four-part extracellular matrix and the microglial five-part synapse support the idea that glial dysfunction plays key roles in the early pathological features common to psychiatric disorders.
“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]
The neural-circuit pruning and refinement section reports that mice lacking the astrocyte pathways had impaired refinement of retinogeniculate connections, supporting a role for astrocytes in circuit development. The concluding remarks discuss possible disease implications as questions for future study; the paper does not establish that glial dysfunction plays a key role in early pathological features common to psychiatric disorders. The four- and five-part synapse concepts are attached to a different citation. (LLM, conf=0.81)
Experimental — accuracy not yet measuredAstrocytes support neurite outgrowth, neuronal survival, synapse formation and synaptic pruning, all vital during brain development.
“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
The Concluding Remarks (page not provided) state that astrocytes contribute to synapse elimination and neural circuit refinement in the developing CNS, supporting the synaptic-pruning part of the claim. The passages found in our copy do not establish that astrocytes support neurite outgrowth, neuronal survival, or synapse formation; the reported numerical comparison concerns astrocytes versus microglia in the developing LGN, not whether astrocytes are the most numerous cell type throughout the mammalian brain. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe phagocytic deficit corresponded with a 90% decrease in Mertk and 60% decrease in Megf10 mRNA.
“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]
ApoE isoforms differentially affect synaptic pruning, with ApoE4 limiting the ability of astrocytes to prune synapses.
“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]
Astrocytes eliminate excess synapses by phagocytosis using the receptors Mertk and Megf10 and indirectly by inducing expression of complement cascade components in neurons.
“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
MERTK plays a minor role in human microglia-mediated synaptic pruning, whereas C1q/CR3 is integral for microglia-mediated synaptic pruning in humans.
“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
Astrocytes participate in circuit refinement by synaptic engulfment of both inhibitory and excitatory synapses through MEGF10 and MERTK pathways during development and in adulthood.
“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
MERTK plays a key role in a variety of phagocytic events, including microglial phagocytosis, macrophage phagocytosis, and phagocytosis by Sertoli cells.
“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).”
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Neurotoxic reactive astrocytes are induced by activated microglia
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Self-citationThe Cellular Phase of Alzheimer’s Disease
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New tools for studying microglia in the mouse and human CNS
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“Microglia also express significantly higher levels of opsonins (Pros1, Gas6) that promote synaptic phagocytosis by astrocytes (49).”
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“That astrocytes are capable of synapse elimination in vitro and in vivo was confirmed by the same group in a later study (334), and it has been hypothesized that disruption of the ability of astrocytes and microglia to eliminate and regulate synapse formation contributes to the pathogenesis of psychiatric disorders (3…”
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Normal aging induces A1-like astrocyte reactivity
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Self-citationMajor depressive disorder: hypothesis, mechanism, prevention and treatment
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BackgroundAstrocytes: a central element in neurological diseases
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BackgroundThe TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer
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Self-citationTranscellular degradation of axonal mitochondria
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BackgroundA complement–microglial axis drives synapse loss during virus-induced memory impairment
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Self-citationCell biology of spinal cord injury and repair
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BackgroundInconsistencies and Controversies Surrounding the Amyloid Hypothesis of Alzheimer's Disease
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BackgroundFunctional roles of reactive astrocytes in neuroinflammation and neurodegeneration
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BackgroundTAM Receptor Signaling in Immune Homeostasis
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BackgroundMicroglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function
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“Astroglia phagocytize synapses in the dLGN to a greater extent than do microglia (69).”
BackgroundSynaptic degeneration in Alzheimer disease
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Self-citationGetting to the Outer Leaflet: Physiology of Phosphatidylserine Exposure at the Plasma Membrane
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BackgroundInfluentialAstrocytes and microglia: In sickness and in health
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BackgroundMitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer
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“In agreement, astrocytes can phagocytose whole synapses (Chung et al., 2013).”
BackgroundAstrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders
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“hiPSC-Astrocytes Display Phagocytic Capacity and Promote Phagocytic Function of Microglia Astrocytes can phagocytose and degrade b-amyloid in AD (Chung et al., 2013; Wyss-Coray et al., 2003).”
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Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia
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“TAM receptors are necessary for astrocyte-mediated synaptic pruning in the visual system, but are dispensable for microglia (Chung et al , 2013).”
InfluentialSleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex
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“…above as potential mediators of the wake-related activation of AP could also apply to microglia, which express both MERTK and C3 receptors (Stevens et al., 2007; Chung et al., 2013) and could be activated by some form of damage at synaptic membranes triggered by sustained neuronal activity.”
BackgroundMethodInfluentialReactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway
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The cell biology of the retinal pigment epithelium
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“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.”
BackgroundThe influence of neuroinflammation in Autism Spectrum Disorder
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Do glia drive synaptic and cognitive impairment in disease?
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Self-citationAstrocytes phagocytose adult hippocampal synapses for circuit homeostasis
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Self-citationMicrobiota alteration is associated with the development of stress-induced despair behavior
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Microglia Function in Central Nervous System Development and Plasticity
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“Along these same lines, it has also recently been shown that, similar to microglia, astrocytes in the retinogeniculate system can also contribute to synaptic pruning by phagocytosing developing synapses in an activity-dependent manner (Chung et al. 2013).”
BackgroundGibson, E. M., Nagaraja, S., Ocampo, A., Tam, L. T., Wood, L. S., Pallegar, P. N., Greene, J. J., Geraghty, A. C., Goldstein, A. K., Ni, L., et al. (2019) · Cell · doi:10.1016/j.cell.2018.10.049 · Cited by 372 · see citing works
Sculpting Neural Circuits by Axon and Dendrite Pruning
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“In adults, astrocytes also engulf cortical synapses, suggesting that astrocytedependent synapse elimination might be a widespread event (Chung et al. 2013).”
BackgroundMicroglia: Architects of the Developing Nervous System
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Astrocyte regulation of synaptic behavior
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Astrocyte Development and HeterogeneityPreprint
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“For example, once considered passive players that provide structural and metabolic support for neurons, astrocytes are now recognized as potent regulators of synapse formation , subsequent fine-tuning, and maintenance (Chung et al. 2013; Clarke and Barres 2013).”
BackgroundBeyond the neuron–cellular interactions early in Alzheimer disease pathogenesis
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Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
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Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
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“Reactive astrocytes effectively engulf dead cells, synapses, and protein aggregates of amyloid (A ) and -SYN (Chang et al., 2000; Magnus et al., 2002; Sokolowski et al., 2011; Lööv et al., 2012; Chung et al., 2013; Fellner et al., 2013; Jones et al., 2013; Söllvander et al., 2016).”
BackgroundNeuron-glia signaling in synapse elimination
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BackgroundErrant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders
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<i>Drosophila</i> Central Nervous System Glia
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“2006), similar to mammalian astrocytes (Chung et al. 2013).”
InfluentialBehaviorally consequential astrocytic regulation of neural circuits
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Phagocytosis in the Brain: Homeostasis and Disease
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“It was initially reported that astrocytes participate in the phagocytosis of synapses utilizing the receptors MerTK and MEGF10, whereby astrocyte-specific deletion of these receptors results in a failure to refine synapses in the developing visual system (26).”
BackgroundArchitecture, Function, and Assembly of the Mouse Visual System
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Immune cells and CNS physiology: Microglia and beyond
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Deciphering the astrocyte reaction in Alzheimer's disease
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“, 2012) and to engulf and eliminate both excitatory and inhibitory synapses during prenatal development, and also in the adult brain (Chung et al., 2013).”
BackgroundThe choreography of neuroinflammation in Huntington's disease
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“In the presence of an insult, astrocytes amplify the inflammatory process initiated by microglia [70], clean up debris [71,72], and take part in repairing the damaged tissue [68].”
BackgroundStructural and Functional Plasticity of Astrocyte Processes and Dendritic Spine Interactions
Pérez‐Alvarez, A., Navarrete, M., Covelo, A., Martín, E. D., & Araque, A. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2401-14.2014 · Cited by 277 · see citing works
Complement System in Neural Synapse Elimination in Development and Disease
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Questions and (some) answers on reactive astrocytes
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BackgroundMicroglia in CNS development: Shaping the brain for the future
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Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders
Sloan, S. A., & Barres, B. A. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.03.005 · Cited by 247 · see citing works
Self-citationMarton, R. M., & Pașca, S. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.11.004 · Cited by 202 · see citing works
Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders
Zengeler, K. E., & Lukens, J. R. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-020-00487-7 · Cited by 254 · see citing works
Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Chung, W.-S., Verghese, P. B., Chakraborty, C., Joung, J., Hyman, B. T., Ulrich, J. D., Holtzman, D. M., & Barres, B. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609896113 · Cited by 242 · see citing works
“Our previous studies have demonstrated that a component of the innate immune system called the classical complement cascade helps to mediate normal developmental CNS synapse elimination (32).”
BackgroundMethodInfluentialSelf-citationAged neutrophils contribute to the first line of defense in the acute inflammatory response
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An astroglial basis of major depressive disorder? An overview
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“…(Bray, 2014; Kriegstein and Alvarez-Buylla, 2009); synapse development, function and plasticity (Allen et al., 2012; Christopherson et al., 2005; Chung et al., 2013; Henneberger, Papouin, Oliet, & Rusakov, 2010; Min and Nevian, 2012; Panatier et al., 2011; Singh et al., 2016; Yang et al.,…”
Background
- 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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.
Cited sources are checked by 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.
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