Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis
Open accessAbstract
Astrocytes are complex glial cells with numerous fine cellular processes that infiltrate the neuropil and interact with synapses. The mechanisms that control the establishment of astrocyte morphology are unknown, and it is unclear whether impairing astrocytic infiltration of the neuropil alters synaptic connectivity. Here we show that astrocyte morphogenesis in the mouse cortex depends on direct contact with neuronal processes and occurs in parallel with the growth and activity of synaptic circuits. The neuroligin family cell adhesion proteins NL1, NL2, and NL3, which are expressed by cortical astrocytes, control astrocyte morphogenesis through interactions with neuronal neurexins. Furthermore, in the absence of astrocytic NL2, the formation and function of cortical excitatory synapses are diminished, whereas inhibitory synaptic function is enhanced. Our findings highlight a previously undescribed mechanism of action for neuroligins and link astrocyte morphogenesis to synaptogenesis. Because neuroligin mutations have been implicated in various neurological disorders, these findings also point towards an astrocyte-based mechanism of neural pathology.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
This could lead to synaptic loss due to excitotoxicity and reduced synaptogenesis due to the destabilization of nascent synapses, which would result in a net loss of synapses during disease progression.
“This could lead to synaptic loss due to excitotoxicity (6, 33, 34) and reduced synaptogenesis due to the destabilization of nascent synapses (16, 17), which would result in a net loss of synapses during disease progression.”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [16]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · cited 1× · see citing works
“9e), indicating that NL2 cKO cells retained their astrocyte identity and did not undergo pathological reactivation characterized by enhanced GFAP expression 6,31 .”
BackgroundA robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907 · see citing works
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 5,508 · see citing works
Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129 · see citing works
Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S. B., Li, G., et al. (2016) · Neuron · doi:10.1016/j.neuron.2015.11.013 · Cited by 2,295 · see citing works
Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis
Christopherson, K. S., Ullian, E. M., Stokes, C. C. A., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., & Barres, B. A. (2005) · Cell · doi:10.1016/j.cell.2004.12.020 · Cited by 1,688 · see citing works
Uniquely Hominid Features of Adult Human Astrocytes
Oberheim, N. A., Takano, T., Han, X., He, W., Lin, J. H. C., Wang, F., Xu, Q., Wyatt, J. D., Pilcher, W., Ojemann, J. G., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4707-08.2009 · Cited by 1,488 · see citing works
Reactive Gliosis and the Multicellular Response to CNS Damage and Disease
Burda, J. E., & Sofroniew, M. V. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.034 · Cited by 1,431 · see citing works
Diversity of astrocyte functions and phenotypes in neural circuits
Khakh, B. S., & Sofroniew, M. V. (2015) · Nature Neuroscience · doi:10.1038/nn.4043 · Cited by 1,239 · see citing works
The neocortical circuit: themes and variations
Harris, K. D., & Shepherd, G. M. G. (2015) · Nature Neuroscience · doi:10.1038/nn.3917 · Cited by 1,215 · see citing works
Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic Specializations via Neuroligins
Graf, E. R., Zhang, X., Jin, S., Linhoff, M. W., & Craig, A. M. (2004) · Cell · doi:10.1016/j.cell.2004.11.035 · Cited by 1,001 · see citing works
Emerging roles of astrocytes in neural circuit development
Clarke, L. E., & Barres, B. A. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3484 · Cited by 975 · see citing works
Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion
Venkatesh, H. S., Johung, T., Caretti, V., Noll, A., Tang, Y., Nagaraja, S., Gibson, E. M., Mount, C., Polepalli, J. S., Mitra, S. S., et al. (2015) · Cell · doi:10.1016/j.cell.2015.04.012 · Cited by 974 · see citing works
Neuroligins Determine Synapse Maturation and Function
Varoqueaux, F., Aramuni, G., Rawson, R. L., Mohrmann, R., Missler, M., Gottmann, K., Zhang, W., Südhof, T. C., & Brose, N. (2006) · Neuron · doi:10.1016/j.neuron.2006.09.003 · Cited by 830 · see citing works
Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors
Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., & Barres, B. A. (2012) · Nature · doi:10.1038/nature11059 · Cited by 764 · see citing works
Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC
Kucukdereli, H., Allen, N. J., Lee, A. T., Feng, A., Ozlu, M. I., Conatser, L. M., Chakraborty, C., Workman, G., Weaver, M., Sage, E. H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104977108 · Cited by 642 · see citing works
Neurexin–neuroligin signaling in synapse development
Craig, A. M., & Kang, Y. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.01.011 · Cited by 640 · see citing works
Neurexin mediates the assembly of presynaptic terminals
Dean, C., Scholl, F. G., Choih, J., DeMaria, S., Berger, J., Isacoff, E., & Scheiffele, P. (2003) · Nature Neuroscience · doi:10.1038/nn1074 · Cited by 617 · see citing works
Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516 · cited 1× · see citing works
“NL dysfunction in disease is postulated to alter the fine balance between inhibition and excitation in the brain 38 .”
BackgroundControl of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling
Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y., & Pasquale, E. B. (2003) · Nature Neuroscience · doi:10.1038/nn994 · Cited by 516 · see citing works
Poulopoulos, A., Aramuni, G., Meyer, G., Soykan, T., Hoon, M., Papadopoulos, T. G., Zhang, M., Paarmann, I., Fuchs, C., Harvey, K., et al. (2009) · Neuron · doi:10.1016/j.neuron.2009.08.023 · Cited by 503 · see citing works
Specification and Morphogenesis of Astrocytes
Freeman, M. R. (2010) · Science · doi:10.1126/science.1190928 · Cited by 489 · see citing works
Srinivasan, R., Lu, T.-Y., Chai, H., Xu, J., Huang, B. S., Golshani, P., Coppola, G., & Khakh, B. S. (2016) · Neuron · doi:10.1016/j.neuron.2016.11.030 · Cited by 443 · see citing works
Norrin/Frizzled4 Signaling in Retinal Vascular Development and Blood Brain Barrier Plasticity
Wang, Y., Rattner, A., Zhou, Y., Williams, J., Smallwood, P. M., & Nathans, J. (2012) · Cell · doi:10.1016/j.cell.2012.10.042 · Cited by 406 · see citing works
Chih, B., Gollan, L., & Scheiffele, P. (2006) · Neuron · doi:10.1016/j.neuron.2006.06.005 · Cited by 393 · see citing works
Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin
Singh, S. K., Stogsdill, J. A., Pulimood, N. S., Dingsdale, H., Kim, Y. H., Pilaz, L., Kim, I. H., Manhães, A. C., Rodrigues, W. D. S., Pamukcu, A., et al. (2016) · Cell · doi:10.1016/j.cell.2015.11.034 · Cited by 311 · see citing works
Self-citationHuman iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia
Windrem, M. S., Osipovitch, M., Liu, Z., Bates, J., Chandler-Militello, D., Zou, L., Munir, J., Schanz, S. J., McCoy, K., Miller, R. H., et al. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.06.012 · Cited by 252 · see citing works
Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour
Ma, Z., Stork, T., Bergles, D. E., & Freeman, M. R. (2016) · Nature · doi:10.1038/nature20145 · Cited by 247 · see citing works
Molecular mechanisms of astrocyte-induced synaptogenesis
Baldwin, K. T., & Eroğlu, Ç. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.05.006 · Cited by 214 · see citing works
Self-citationThe cellular and molecular landscape of neuroligins
Bemben, M. A., Shipman, S. L., Nicoll, R. A., & Roche, K. W. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.06.004 · Cited by 171 · see citing works
Visual Experience before Eye-Opening and the Development of the Retinogeniculate Pathway
Akerman, C. J., Smyth, D., & Thompson, I. D. (2002) · Neuron · doi:10.1016/s0896-6273(02)01010-3 · Cited by 152 · see citing works
Morel, L., Higashimori, H., Tolman, M., & Yang, Y. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1167-14.2014 · Cited by 151 · see citing works
Sun, C., Cheng, M.-C., Qin, R., Liao, D., Chen, T.-T., Koong, F., Chen, G., & Chen, C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr208 · Cited by 129 · see citing works
Liang, J., Xu, W., Hsu, Y.-T., Yee, A. X., Chen, L., & Südhof, T. C. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.31 · Cited by 110 · see citing works
Stichel, C. C., M�ller, C. M., & Zilles, K. (1991) · Journal of Neurocytology · doi:10.1007/bf01279614 · Cited by 100 · see citing works
Membrane-Tethered Monomeric Neurexin LNS-Domain Triggers Synapse Formation
Gökçe, Ö., & Südhof, T. C. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1232-13.2013 · Cited by 96 · see citing works
Synaptogenesis in the developing mouse visual cortex
Ming-shan, L., Cui, Z., Niu, Y., Liu, B., Fan, W., Yu, D., & Deng, J. (2009) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2009.08.028 · Cited by 80 · see citing works
SnapShot: Neuroligin-Neurexin Complexes
Baudouin, S., & Scheiffele, P. (2010) · Cell · doi:10.1016/j.cell.2010.05.024 · Cited by 63 · see citing works
Neuroligin 1 Induces Blood Vessel Maturation by Cooperating with the α6 Integrin
Samarelli, A. V., Riccitelli, E., Bizzozero, L., Silveira, T. N., Seano, G., Pergolizzi, M., Vitagliano, G., Cascone, I., Carpentier, G., Bottos, A., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.530972 · Cited by 43 · see citing works
Proctor, D. T., Stotz, S. C., Scott, L. O. M., de la Hoz, C. L. R., Poon, K. W. C., Stys, P. K., & Colicos, M. A. (2015) · Glia · doi:10.1002/glia.22875 · Cited by 39 · see citing works
Neuroligins Provide Molecular Links Between Syndromic and Nonsyndromic Autism
Singh, S. K., & Eroğlu, Ç. (2013) · Science Signaling · doi:10.1126/scisignal.2004102 · Cited by 35 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Synaptic proximity enables NMDAR signalling to promote brain metastasis
Zeng, Q., Michael, I. P., Zhang, P., Saghafinia, S., Knott, G., Jiao, W., McCabe, B. D., Galván, J. A., Robinson, H. P. C., Zlobec, I., et al. (2019) · Nature · doi:10.1038/s41586-019-1576-6 · Cited by 574 · see citing works
Molecular basis of astrocyte diversity and morphology across the CNS in health and disease
Endo, F., Kasai, A., Soto, J. S., Yu, X., Qu, Z., Hashimoto, H., Gradinaru, V., Kawaguchi, R., & Khakh, B. S. (2022) · Science · doi:10.1126/science.adc9020 · Cited by 560 · see citing works
Lau, S.-F., Cao, H., Fu, A. K. Y., & Ip, N. Y. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008762117 · Cited by 476 · see citing works
Sadick, J. S., O’Dea, M. R., Hasel, P., Dykstra, T., Faustin, A., & Liddelow, S. A. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.008 · Cited by 415 · see citing works
Schiweck, J., Eickholt, B. J., & Murk, K. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00261 · Cited by 223 · see citing works
Comparative transcriptomics reveals human-specific cortical features
Jorstad, N. L., Song, J. H. T., Exposito-Alonso, D., Suresh, H., Castro-Pacheco, N., Krienen, F. M., Yanny, A. M., Close, J., Gelfand, E., Long, B., et al. (2023) · Science · doi:10.1126/science.ade9516 · Cited by 208 · see citing works
The aryl hydrocarbon receptor and the gut–brain axis
Barroso, A., Mahler, J. V., Fonseca-Castro, P. H., & Quintana, F. J. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00585-5 · Cited by 152 · see citing works
The Many Faces of Astrocytes in Alzheimer's Disease
Monterey, M. D., Wei, H., Wu, X., & Wu, J. Q. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.619626 · Cited by 117 · see citing works
Cordaro, M., Cuzzocrea, S., & Crupi, R. (2020) · Antioxidants · doi:10.3390/antiox9030216 · Cited by 98 · see citing works
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
Windham, I. A., Powers, A. E., Ragusa, J. V., Wallace, E. D., Zanellati, M. C., Williams, V. H., Wagner, C. H., White, K. K., & Cohen, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202305003 · Cited by 96 · see citing works
Human neuronal maturation comes of age: cellular mechanisms and species differences
Wallace, J. L., & Pollen, A. A. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00760-3 · Cited by 82 · see citing works
Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
Staurenghi, E., Giannelli, S., Testa, G., Sottero, B., Leonarduzzi, G., & Gamba, P. (2021) · Antioxidants · doi:10.3390/antiox10121890 · Cited by 44 · see citing works
Wang, L., Guo, Q., Acharya, S., Zheng, X., Huynh, V., Whitmore, B., Yimit, A., Malhotra, M., Chatterji, S., Rosin, N., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01726-z · Cited by 33 · see citing works
Walker, C. D., Sexton, H. G., Hyde, J., Greene, B., & Risher, M.-L. (2022) · Cells · doi:10.3390/cells11193111 · Cited by 13 · see citing works
Chimeric brain models to study human glial-neuronal and macroglial-microglial interactions
Jin, M., Ma, Z., Zhang, H., Dang, R., Papetti, A. V., Stillitano, A. C., Zou, L., Goldman, S. A., & Jiang, P. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116794 · Cited by 6 · see citing works
- Authors
- Stogsdill, J. A., Ramirez, J., Liu, D., Kim, Y. H., Baldwin, K. T., Enustun, E., Ejikeme, T., Ji, R.-R., & Eroglu, C.
- Affiliations
- Duke Medical Center (US)
- Duke University (US)
- Venue
- Nature
- Published
- 2017-11
- Volume
- 551
- Issue
- 7679
- Pages
- 192-197
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5796651
- OpenAlex
- W2767960938
- Cited by
- 506
- References
- 41
- Citations by year
- 2026: 50 · 2025: 67 · 2024: 72 · 2023: 79 · 2022: 61 · 2021: 52 · 2020: 59 · 2019: 46 · 2018: 19 · 2017: 1
- FWCI
- 16.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Hartwell Foundation
- National Institute for Health and Care Research
- National Institutes of Health
- National Institute on Drug Abuse (R01DA031833)
- National Institute of General Medical Sciences (T32GM007184)
- National Institute of Neurological Disorders and Stroke (F31NS092419)
- National Institute of Dental and Craniofacial Research (R01DE022743)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- astrocytes, neuroligins, synaptogenesis, neurexin, adhesion molecules, cortical astrocytes, excitatory synapses, inhibitory synapses, astrocyte-neuron interaction, synaptic density, neurological disorders
- MeSH terms
- Animals, Astrocytes, Cerebral Cortex, Neural Inhibition, Receptors, Cell Surface, Synapses, Cell Adhesion Molecules, Neuronal, Neural Cell Adhesion Molecules, Cell Shape, Mice
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
