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Cited by 332Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

Neuron-glia signaling in synapse elimination

Open access
Wilton, Daniel K., Dissing-Olesen, Lasse, Stevens, Beth·2019·Annual Review of Neuroscience
DOI 10.1146/annurev-neuro-070918-050306
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Abstract

Maturation of neuronal circuits requires selective elimination of synaptic connections. Although neuron-intrinsic mechanisms are important in this process, it is increasingly recognized that glial cells also play a critical role. Without proper functioning of these cells, the number, morphology, and function of synaptic contacts are profoundly altered, resulting in abnormal connectivity and behavioral abnormalities. In addition to their role in synaptic refinement, glial cells have also been implicated in pathological synapse loss and dysfunction following injury or nervous system degeneration in adults. Although mechanisms regulating glia-mediated synaptic elimination are still being uncovered, it is clear this complex process involves many cues that promote and inhibit the removal of specific synaptic connections. Gaining a greater understanding of these signals and the contribution of different cell types will not only provide insight into this critical biological event but also be instrumental in advancing knowledge of brain development and neural disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that microglia, astrocytes, Schwann cells, and other glia actively eliminate synapses during development and can contribute to pathological synapse loss in injury and neurodegenerative disease. It highlights conserved molecular pathways that promote or restrain glial engulfment, including complement, TREM2, MEGF10/MERTK, CD47-SIRPα, fractalkine, IL33, hevin/SPARC, Nfasc155, and NRG1 type III.

Key findings

  • Glial cells are required for normal developmental synapse elimination: at the rodent neuromuscular junction, motor end plates are initially innervated by up to 10 inputs and are pruned over the first few postnatal weeks; cerebellar climbing fibers are removed over the first postnatal week; and retinogeniculate eye-specific segregation occurs during the first postnatal week in mice.
  • Microglia and astrocytes engulf synaptic material through pathways including complement C1q/C3–CR3, TREM2/DAP12, MEGF10/MERTK, CX3CR1, autophagy, and IL33; negative regulators such as CD47–SIRPα protect specific inputs from excess pruning.
  • Schwann cells contribute to synapse elimination at the NMJ via Nfasc155, terminal Schwann cell processes, phagocytosis, and NRG1 type III signaling; Nfasc155 conditional KO mice show many NMJs still multi-innervated at p11, and hevin-KO mice retain spines with multiple excitatory contacts at postnatal day 25.
  • Pathological synapse loss in Alzheimer’s models, tauopathy, FTD, glaucoma, and West Nile virus infection involves complement and microglia, suggesting reactivation of developmental elimination programs; C3 ablation preserved synapses and improved water T-maze performance despite increased Aβ plaques in APP/PS1 mice, and C1q blockade prevented RGC death and optic nerve damage in glaucoma.

Methods

  • Narrative review; no primary experimental design or new data are reported.
  • Synthesizes mechanistic studies across rodents, Drosophila, C. elegans, Xenopus, zebrafish, cultured cells, and human genetic/transcriptomic/neuroimaging literature.
  • Main analysis is thematic synthesis of neuron-glia signaling pathways that promote or inhibit synapse elimination during development, injury, and disease.

Limitations

  • The paper states that no studies directly demonstrate glia-mediated synaptic elimination in human disease; human relevance remains to be convincingly demonstrated.
  • The paper states that most studies focus on sensory circuits, leaving relevance to higher cognitive brain regions unresolved; negative regulators of astrocytic or Schwann cell-mediated elimination have not been identified, and many downstream mechanisms remain unclear.
  • Evident from the text: as a review, conclusions rely on cited model-organism, in vitro, and conditional knockout studies rather than new primary evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1146/annurev-neuro-070918-050306

Cites

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    Removal of excess connections is necessary for the maturation and refinement of circuits and connections in the nervous system.

    “many studies have shown that their removal is necessary for the maturation and refinement of circuits and connections in the nervous system (Colman & Lichtman 1993, Kano & Hashimoto 2009, Lichtman & Colman 2000, Riccomagno & Kolodkin 2015).”
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    • cites Kano & Hashimoto 2009

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    • cites Lichtman & Colman 2000

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    Pathological synaptic loss is a hallmark of many neurodegenerative diseases and different types of neural injury.

    “Conversely, pathological synaptic loss is a hallmark of many neurodegenerative diseases as well as different types of neural injury.”
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    • cites DeKosky & Scheff 1990

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    • cites Graveland et al. 1985

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    • cites Selkoe 2002

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  • Premisecitation

    Elimination of excess or unnecessary synaptic connections is an important process in the development of both the central and peripheral nervous systems.

    “Elimination of excess or unnecessary synaptic connections is an important process in the development of both the central and peripheral nervous systems (CNS and PNS, respectively).”
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    • cites Colman & Lichtman 1993

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    • cites Kano & Hashimoto 2009

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    • cites Lichtman & Colman 2000

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    Engulfment of presynaptic retinal inputs peaks early in postnatal development during periods of eye-specific segregation and synaptic refinement in the dLGN.

    “Recent work in the developing visual system revealed that the engulfment of presynaptic retinal inputs peaks early in postnatal development during periods of eye-specific segregation and synaptic refinement in the dLGN (Schafer et al. 2012).”
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    Ablating glial cells or manipulating their biology leads to persistent excess synaptic connections in adulthood with corresponding changes to neural circuits and behavior.

    “Ablating these cells or manipulating their biology leads to persistent excess synaptic connections in adulthood with corresponding changes to neural circuits and behavior (Figure 1).”
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    Premisecitation

    Synapse loss is an early pathological event that increases in line with the progression of clinical symptoms.

    “Studies on postmortem tissues have shown this loss to be an early pathological event that increases in line with the progression of clinical symptoms (DeKosky & Scheff 1990, Graveland et al. 1985, Selkoe 2002, Terry et al. 1991, Wishart et al. 2006).”
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    Premisecitation

    Complement proteins C1q and C3 localize to subsets of synapses and promote engulfment of synaptic material through interaction with the microglia-specific C3 receptor (CR3).

    “In the brain, complement proteins C1q and C3 localize to subsets of synapses and promote engulfment of synaptic material through interaction with the microglia-specific C3 receptor (CR3).”
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    • cites Schafer et al. 2012

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    • cites Stevens et al. 2007

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    Premisecitation

    Synapse loss is a common event in many forms of neural damage and correlates with cognitive dysfunction in Alzheimer's and other diseases.

    “it is a common event in many forms of neural damage and correlates with cognitive dysfunction in Alzheimer's and other diseases.”
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    Premisecitation

    Mice lacking complement molecules have deficits in RGC axon arbor segregation, maturation of synaptic connections, and excess RGC inputs on postsynaptic neurons.

    “Correspondingly, mice lacking these molecules have deficits in RGC axon arbor segregation, maturation of synaptic connections, and excess RGC inputs on postsynaptic neurons (Schafer et al. 2012, Stevens et al. 2007) (Figures 1 and 2).”
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    Premisecitation

    Genetic and pharmacological disruption or elimination of microglia alters the number of synaptic structures in the adult and changes both neural circuitry and behavior.

    “Indeed, genetic and pharmacological disruption or elimination of microglia alters the number of synaptic structures in the adult and changes both neural circuitry and behavior (Filipello et al. 2018, Ji et al. 2013, Nelson & Lenz 2017, Paolicelli et al. 2011, Parkhurst et al. 2013, Schafer et al. 2012, Torres et al. 2016, Zhan et al. 2014).”
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    Several mechanistic studies in model organisms have revealed the involvement of many glial signaling pathways and molecular mediators that both promote and constrain synaptic elimination, enabling the selective removal of specific synaptic populations and the sculpting of precise neuronal circuits.

    “Several mechanistic studies in model organisms have revealed the involvement of many glial signaling pathways and molecular mediators that both promote and constrain synaptic elimination, enabling the selective removal of specific synaptic populations and the sculpting of precise neuronal circuits (Chung & Barres 2012, Hammond et al. 2018b, Neniskyte & Gross 2017, Salter & Stevens 2017).”
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    Interpretationreasoning

    Genetically ablating complement components does not completely prevent arbor segregation or synaptic loss, suggesting the existence of other mediators.

    “However, genetically ablating complement components does not completely prevent arbor segregation or synaptic loss, suggesting the existence of other mediators.”
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    Premisecitation

    C1q-knockout mice have a higher axonal bouton density in layer 5 of the sensorimotor cortex and a propensity toward spontaneous atypical absence seizures, suggesting that complement plays a broader role in establishing appropriate connectivity in the adult brain.

    “C1q-knockout (KO) mice also have a higher axonal bouton density in layer 5 of the sensorimotor cortex and a propensity toward spontaneous atypical absence seizures, suggesting that complement plays a broader role in establishing appropriate connectivity in the adult brain (Chu et al. 2010, Ma et al. 2013).”
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    Some changes in microglial biology observed in TREM2-KO mice include reductions in cell numbers and lysosomal protein levels and abnormal cell morphologies.

    “some of the changes in microglial biology observed in TREM2-KO mice include reductions in cell numbers and lysosomal protein levels and abnormal cell morphologies.”
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    In the absence of TREM2, microglia take up less synaptic proteins, and there is a transient increase in synaptic marker levels, dendritic spine numbers, and electrophysiological measurements of synaptic input.

    “In its absence, microglia take up less synaptic proteins, and there is a transient increase in synaptic marker levels, dendritic spine numbers, and electrophysiological measurements of synaptic input (Filipello et al. 2018).”
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    Microglial TREM2 appears to respond to a specific signal present on the material being engulfed, as its ability to regulate spine numbers and functional connectivity is only observed when microglia directly contact neuronal membranes.

    “Interestingly, microglial TREM2 appears to respond to a specific signal present on the material being engulfed, as its ability to regulate spine numbers and functional connectivity is only observed when microglia directly contact neuronal membranes (Filipello et al. 2018).”
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    This decline coincides with reduced connectivity, measured by fMRI, and an impairment in repetitive and social behaviors.

    “This coincides with reduced connectivity, measured by blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI), and an impairment in repetitive and social behaviors (Filipello et al. 2018).”
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    Despite the initial increase in synaptic input in TREM2-KO mice, these connections appear to be unstable, and in the adult synapse numbers decline below the level of wild-type littermates.

    “Despite the initial increase in synaptic input in TREM2-KO mice, these connections appear to be unstable, and in the adult synapse, numbers decline below the level of wild-type littermates.”
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    Premisecitation

    Homozygous loss-of-function mutations in TREM2 or its signaling adaptor DAP12 cause the autosomal recessive disorder Nasu-Hakola disease.

    “Of note, homozygous loss-of-function mutations in TREM2 or its signaling adaptor DAP12 cause the autosomal recessive disorder Nasu-Hakola disease (a neurodegenerative disorder somewhat similar to frontal-type dementia)”
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    In mice deficient in microglial Atg7, spine numbers were increased and mice developed a variety of deficits in social behavior.

    “In mice deficient in microglial Atg7, which is required for the formation of autophagic vesicles to shuttle material to lysosomes, spine numbers were increased and mice developed a variety of deficits in social behavior (Kim et al. 2017, Lieberman et al. 2019).”
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    In culture paradigms, TDP-43 regulates expression of lysosomal proteins as well as the phagocytosis of protein aggregates.

    “In culture paradigms, TDP-43, a transcriptional repressor, regulates expression of lysosomal proteins as well as the phagocytosis of protein aggregates (Paolicelli et al. 2017) (Figure 2).”
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    Premisecitation

    Signaling by CD47 on neuronal membranes to its receptor SIRPα on microglia suppresses the phagocytosis of synaptic material, and mice lacking either protein exhibit excess microglial engulfment, overpruning, and loss of dLGN synapses.

    “Signaling by CD47 on neuronal membranes to its receptor, SIRPα, on microglia suppresses the phagocytosis of synaptic material, and mice lacking either protein exhibit excess microglial engulfment, overpruning, and loss of dLGN synapses (Lehrman et al. 2018) (Figure 2).”
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    The don't eat me signal CD47, enriched in the developing visual thalamus during the peak of synaptic pruning, acts as a protective molecule.

    “A recent study identified the don't eat me signal CD47, a transmembrane immunoglobulin superfamily protein enriched in the developing visual thalamus during the peak of synaptic pruning, as one such protective molecule (Lehrman et al. 2018).”
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    Premisecitation

    In the hippocampus, microglia often wrap around and encapsulate dendritic spines but do not separate them from the dendrite or phagocytose elements of the postsynaptic neuron.

    “The study found that, in the hippocampus, microglia often wrap around and encapsulate dendritic spines but do not separate them from the dendrite or phagocytose elements of the postsynaptic neuron.”
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    Premisecitation

    Presynaptic elements are phagocytosed, with evidence of both axonal and presynaptic material in the process of being engulfed.

    “In contrast, presynaptic elements are phagocytosed, with evidence of both axonal and presynaptic material in the process of being engulfed.”
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    Conditional ablation of TDP-43 from microglia reduces cortical levels of excitatory synapse markers as well as the number of dendritic spines in adult mice.

    “In line with these findings, the conditional ablation of TDP-43 from microglia reduces cortical levels of excitatory synapse markers as well as the number of dendritic spines in adult mice (Paolicelli et al. 2017).”
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    Premisecitation

    This impairment is in part mediated by a reduction in ATP release from astrocytes, as intracerebroventricular injection of ATP or an agonist of its receptor on neurons rescues synaptic elimination.

    “This is in part mediated by a reduction in ATP release from astrocytes, as intracerebroventricular injection of ATP or an agonist of its receptor on neurons rescues synaptic elimination (Yang et al. 2016).”
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    The glycoprotein hevin (SPARCL1), secreted by astrocytes and localizes to excitatory synapses, is a crucial mediator of synaptic refinement.

    “The glycoprotein hevin (SPARCL1), which is secreted by astrocytes and localizes to excitatory synapses, is another crucial mediator of synaptic refinement (Risher et al. 2014) (Figure 2).”
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    In hevin-KO mice, spines with multiple excitatory contacts from both the thalamus and cortex are still present at postnatal day 25, suggesting that competition for postsynaptic territory remains unresolved.

    “In hevin-KO mice, spines with multiple excitatory contacts from both the thalamus and cortex are still present at postnatal day 25, suggesting that competition for postsynaptic territory remains unresolved (Risher et al. 2014).”
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    Premisecitation

    Mice deficient in the astrocyte-specific phagocytic receptor MEGF10 or MERTK have deficiencies in eye-specific segregation of RGC axon arbors, similar to complement-deficient mice, and a greater number of weaker functional inputs onto individual relay neurons.

    “Mice deficient in the astrocyte-specific phagocytic receptor MEGF10 (which has orthologs in Drosophilia and Caenorhabditis elegans; see below) or MERTK, which is more broadly expressed, have deficiencies in eye-specific segregation of RGC axon arbors, similar to complement-deficient mice, and a greater number of weaker functional inputs onto individual relay neurons (Chung et al. 2013).”
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    Like microglia, astrocytes engulf synaptic material, and blocking or inhibiting engulfment impairs refinement of visual circuits.

    “Like microglia, astrocytes engulf synaptic material, and blocking or inhibiting engulfment impairs refinement of visual circuits (Figures 1 and 2).”
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    Premisecitation

    Hevin facilitates the interaction of presynaptic Nrx1a and postsynaptic NL1 and is required for the formation of excitatory inputs in the visual cortex, but at later stages it also regulates the removal of some of these connections.

    “It facilitates the interaction of presynaptic Nrx1a and postsynaptic NL1 and is required for the formation of excitatory inputs in the visual cortex, but at later stages it also regulates the removal of some of these connections (Risher et al. 2014, Singh et al. 2016).”
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    Premisecitation

    Ablating MERTK causes a transient increase in microglial engulfment, suggesting that microglia can compensate for reduced astrocyte phagocytosis.

    “Interestingly, ablating MERTK causes a transient increase in microglial engulfment, suggesting that microglia can compensate for reduced astrocyte phagocytosis (Chung et al. 2013).”
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    Its receptor Ilrl1 is expressed specifically on microglia, and conditional knockouts of IL33 and ILRL1 phenocopy one another, with more excitatory synaptic inputs in these circuits and a hyperexcitable phenotype.

    “Its receptor, Ilrl1, is expressed specifically on microglia, and conditional knockouts of IL33 and ILRL1 phenocopy one another, with more excitatory synaptic inputs in these circuits and a hyperexcitable phenotype (Vainchtein et al. 2018).”
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    SPARC is expressed by many glial cells and mediates synapse elimination in the PNS of Xenopus tropicalis tadpoles by disassembling NMJs and retracting mature axon terminals.

    “SPARC is expressed by many glial cells and mediates synapse elimination in the PNS of Xenopus tropicalis tadpoles by disassembling NMJs and retracting mature axon terminals (Lopez-Murcia et al. 2015, Vincent et al. 2008).”
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    Treating mice with lipopolysaccharide prompts the release of inflammatory cytokines from microglia, which causes a transcriptional change in astrocytes that impairs many of their biological functions, including their ability to engulf synaptic material.

    “Treating mice with lipopolysaccharide prompts the release of inflammatory cytokines from microglia, which causes a transcriptional change in astrocytes that impairs many of their biological functions, including their ability to engulf synaptic material (Liddelow et al. 2017).”
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    Overexpression of NRG1 type III increases the number of terminal Schwann cells at the NMJ and accelerates the elimination of synapses.

    “Overexpression of NRG1 type III, a Schwann cell mitogen, increases the number of terminal Schwann cells at the NMJ and accelerates the elimination of synapses (Lee et al. 2016).”
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    Following ablation, there is a significant increase in synapses present on Purkinje cell bodies and a corresponding increase in the excitatory neuronal response to glutamate uncaging.

    “Following ablation, there is a significant increase in synapses present on Purkinje cell bodies and a corresponding increase in the excitatory neuronal response to glutamate uncaging.”
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    Premisecitation

    During periods of remodeling, processes from terminal Schwann cells separate axon terminals from the muscle fiber, forming tight contacts with the plaque of acetylcholine receptors and limiting the area for synaptic contact.

    “Ultrastructural studies have found that, during periods of remodeling, processes from these cells separate axon terminals from the muscle fiber, forming tight contacts with the plaque of acetylcholine receptors and limiting the area for synaptic contact (Smith et al. 2013).”
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    Inhibiting NRG1 type III signaling by genetically removing one of the key enzymes involved in its processing results in fewer terminal Schwann cells and a delay in the reduction of polyneuronally innervated NMJs.

    “Conversely, inhibiting NRG1 type III signaling by genetically removing one of the key enzymes involved in its processing results in fewer terminal Schwann cells and a delay in the reduction of polyneuronally innervated NMJs (Lee et al. 2016).”
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    This delay in synapse elimination is due to aberrations in cytoskeletal transport within axons, resulting in lower levels of neurofilament light chains at the NMJ.

    “This delay in synapse elimination is due to aberrations in cytoskeletal transport within axons, resulting in lower levels of neurofilament light chains at the NMJ (Roche et al. 2014).”
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    Premisecitation

    Conditional ablation of Nogo-A in oligodendrocytes increases dendritic spine density and length in motor cortex pyramidal cells, suggesting a possible deficit in developmental synapse elimination or regressive events.

    “Conditional ablation of Nogo-A in oligodendrocytes increases dendritic spine density and length in motor cortex pyramidal cells, suggesting a possible deficit in developmental synapse elimination or regressive events (Zemmar et al. 2018).”
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    Premisecitation

    Some of these mechanisms differ from those employed by astrocytes to engulf apoptotic cells, suggesting that the pathways engaged are context dependent and correlate with the type of destructive program required.

    “Interestingly, some of these mechanisms differ from those employed by astrocytes to engulf apoptotic cells, suggesting that the pathways engaged are context dependent and correlate with the type of destructive program required (Awasaki et al. 2006, Tasdemir-Yilmaz & Freeman 2014).”
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    Premisecitation

    Both possess immunoreceptor tyrosine-based inhibitory motifs but Draper II's binding partner corkscrew is an ortholog of SHP-1, a binding partner of Sirpα.

    “Not only do both possess immunoreceptor tyrosine-based inhibitory motifs but Draper II's binding partner corkscrew is an ortholog of SHP-1, a binding partner of Sirpα (Fujioka et al. 1996, Kharitonenkov et al. 1997, Logan et al. 2012, Matozaki et al. 2009).”
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    Draper II shares several parallels with vertebrate Sirpα, which, together with its ligand CD47, prevents excess microglial engulfment in the developing visual system.

    “Draper II shares several interesting parallels with vertebrate Sirpα, which, together with its ligand CD47, prevents excess microglial engulfment in the developing visual system (Lehrman et al. 2018).”
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    Loss of these signaling components increases the number of excitatory synapses that form on the muscle wall and exacerbates convulsion behavior in an induced seizure model.

    “The loss of these signaling components increases the number of excitatory synapses that form on the muscle wall and exacerbates convulsion behavior in an induced seizure model.”
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    GABAergic inhibitory synapse numbers are normally unaffected, but misexpression of ZIG-10 in these inhibitory motor neurons brings them under the control of epidermal CED-1 activity, suggesting that ZIG-10 enables the specific targeting of excitatory synapses for epidermal phagocytic activity.

    “Intriguingly, GABAergic inhibitory synapse numbers are normally unaffected, but misexpression of ZIG-10 in these inhibitory motor neurons brings them under the control of epidermal CED-1 activity, suggesting that ZIG-10 enables the specific targeting of excitatory synapses for epidermal phagocytic activity (Cherra & Jin 2016).”
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    Interpretationreasoning

    Both pro-engulfment pathways and negative regulators of glial phagocytosis are conserved.

    “This suggests that both pro-engulfment pathways and negative regulators of glial phagocytosis are conserved.”
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    Other studies have demonstrated the capacity of C. elegans glia to alter both the molecular repertoire and the morphology of neurons; however, the mechanisms underlying these events remain unclear.

    “Other studies have demonstrated the capacity of C. elegans glia to alter both the molecular repertoire and the morphology of neurons; however, the mechanisms underlying these events remain unclear (Shaham 2015).”
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    • cites Shaham 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Visual experience alters microglial association with dendritic spines and their phagocytic activity in the visual cortex.

    “Visual experience also appears to alter microglial association with dendritic spines as well as their phagocytic activity in the visual cortex.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Tremblay et al. 2010

      Not checked in the free run.

    • cites Sipe et al. 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD47 functions as a negative regulator of microglial engulfment in the developing visual system and mediates neuronal activity-dependent changes in engulfment.

    “CD47, which functions as a negative regulator of microglial engulfment in the developing visual system, was recently shown to mediate neuronal activity-dependent changes in engulfment (Lehrman et al. 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lehrman et al. 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic ablation of complement component C3 preserves synaptic structures and improves cognitive performance in the water T-maze despite an increase in Aβ plaques in the APP/PS1 mouse model.

    “Supporting this idea, genetic ablation of complement component C3 was found to preserve synaptic structures and improve cognitive performance in the water T-maze despite an increase in the number of Aβ plaques (APP/PS1 mouse model) (Shi et al. 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shi et al. 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In ASD, studies have shown an increased number of synaptic connections in specific brain regions, suggesting deficits in synaptic pruning and refinement.

    “In the case of autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by difficulties with communication and social interaction as well as repetitive behaviors, studies have shown an increased number of synaptic connections in specific brain regions, suggesting deficits in synaptic pruning and refinement (Hutsler & Zhang 2010, Lewis et al. 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hutsler & Zhang 2010

      Not checked in the free run.

    • cites Lewis et al. 2013

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    Premisecitation

    Ablating C3 or its microglial receptor C3aR preserves presynaptic marker levels and reduces microglial engulfment of synaptic elements in WNV-infected mice.

    “In line with this, ablating C3 or its microglial receptor, C3aR, preserves presynaptic marker levels and reduces the microglial engulfment of synaptic elements (Vasek et al. 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vasek et al. 2016

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Despite the complexity and diversity of the signals involved, mechanisms of glia-mediated synaptic elimination are highly conserved between species and among vastly different biological contexts.

    “Interestingly, despite the complexity and diversity of the signals involved, mechanisms of glia-mediated synaptic elimination are highly conserved between species and among vastly different biological contexts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    All these data together with mouse model studies suggest that glia-mediated synaptic elimination may be operating in the diseases and neurodevelopmental disorders described in this review, but this remains to be convincingly demonstrated.

    “All of these data, together with the mouse model studies of these neurodegenerative diseases outlined above, suggest that glia-mediated synaptic elimination may be operating in the diseases and neurodevelopmental disorders described in this review; however, due to the complexities of studying human disease and the limitations of the tools currently available, this remains to be convincingly demon”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Transcriptomic studies identified two modules of coexpressed genes enriched in autistic brains: a neuronal module enriched for susceptibility and synaptic genes, and a module enriched for immune genes and glial markers.

    “The relevance of glia to these putative pruning deficits has mostly come from transcriptomic studies, which identified two modules of coexpressed genes enriched in autistic brains.The first is a neuronal module enriched for known susceptibility genes as well as synaptic genes, and the second is a module enriched for immune genes and glial markers (Gandal et al. 2018, Voineagu et al. 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Gandal et al. 2018

      Not checked in the free run.

    • cites Voineagu et al. 2011

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    Premisecitation

    The pathology of schizophrenia has been associated with synaptic deficits and immune system dysregulation.

    “The pathology of schizophrenia, a neuropsychiatric disorder characterized by impaired cognition and perception, has also been associated with synaptic deficits and immune system dysregulation (Feinberg 1982, Gardiner et al. 2013, Glantz & Lewis 2000, Kolluri et al. 2005, Sekar et al. 2016, Xu et al. 2012, Zhang et al. 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Feinberg 1982

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    • cites Gardiner et al. 2013

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    • cites Glantz & Lewis 2000

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53 of 53

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?

  • Microglial cells play a critical role in the elimination of excess or unnecessary synaptic connections, which is necessary for the maturation and refinement of circuits and connections in the nervous system.

    “glial cells, especially microglial cells, have been increasingly recognized to play a critical role in the elimination of excess or unnecessary synaptic connections, which is necessary for the maturation and refinement of circuits and connections in the nervous system (101, 102).”

    From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [102]

  • SCFAs may improve neuronal homeostasis and function by influencing neurotrophic factors such as nerve growth factor, glial cell line-derived neurotrophic factor, and BDNF.

    “SCFAs may also improve neuronal homeostasis and function by influencing neurotrophic factors such as nerve growth factor, glial cell line-derived neurotrophic factor, and BDNF (119–122).”

    From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [119]

The citation lists haven’t been fetched yet

References 162 · Cited by 332

Research works printed but not linked: 1

  1. Borroni B, 2014, Neurobiol. Aging, 35, e7

Authors
Wilton, D. K., Dissing-Olesen, L., & Stevens, B.
Affiliations
  • Boston Children's Hospital (US)
  • Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
  • Broad Institute (US)
Corresponding author
Stevens, Beth
ORCID
Venue
Annual Review of Neuroscience
Publisher
Annual Reviews
Published
2019-07-08
Volume
42
Issue
1
Pages
107-127
ISSN
  • 0147-006X (ISSN-L)
  • 1545-4126
DOI
10.1146/annurev-neuro-070918-050306
OpenAlex
W2959600977
Semantic Scholar
d129b0f5cdc40a971bdfb129fefbd45bfcbf325a
Cited by
332
References
162
Citations by year
2026: 24 · 2025: 40 · 2024: 62 · 2023: 52 · 2022: 55 · 2021: 62 · 2020: 33 · 2019: 4
FWCI
5.12
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Lundbeckfonden (R182-2014-2844)
  • H. Lundbeck A/S
  • National Institute of Neurological Disorders and Stroke (R01NS084298, R01NS092578)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
synaptic pruning, glial cells, neuron-glia signaling, synaptic refinement, neural circuit maturation, synaptic loss, neurodegeneration, brain development, neurological disorders
MeSH terms
Animals, Astrocytes, Central Nervous System, Cues, Biological Evolution, Humans, Invertebrates, Morphogenesis, Myelin Sheath, Nerve Degeneration, Nervous System Diseases, Neuroglia, Neuromuscular Junction, Neurons, Synapses, Microglia, Peripheral Nervous System, Exosomes

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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 2026-10-09.

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