Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice
Open accessAbstract
The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia. Overexpression of complement C4A is associated with schizophrenia risk. Using a novel mouse model, Yilmaz et al. find that increased expression of C4A leads to abnormal synaptic pruning and behavior, suggesting its importance as a therapeutic target.
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?
Proteins of the complement cascade (including C1q, C3, and C4) and members of MHCI (including H2-K and H2-D) contribute to synapse elimination in the developing visual system.
“proteins of the complement cascade (including C1q, C3, and C4) and members of MHCI (including H2-K and H2-D) contribute to synapse elimination in the developing visual system.20,21,22,23,24,25”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [25]
Many immune proteins have non-immune roles in the healthy nervous system, where they are required for normal neuronal development, dendritic morphology, and synaptic transmission.
“many immune proteins have non-immune roles in the healthy nervous system, where they are required for normal neuronal development, dendritic morphology, and synaptic transmission.”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [25]
A growing number of immune proteins have been identified that play central roles in neuronal homeostasis, where they negatively regulate neurite length, dendritic complexity, and synaptic transmission, and many are upregulated by TLR9.
“A growing number of immune proteins have been identified that play central roles in neuronal homeostasis, where they negatively regulate neurite length, dendritic complexity, and synaptic transmission,20,21,22,23,24,25,26,27,28,29,45,46,48,72,73,74,75,76,77,78,79 and many are upregulated by TLR9.”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [25]
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
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
Aligning sequence reads, clone sequences and assembly contigs with BWA-MEMPreprint
Li, H. (2013) · arXiv (Cornell University) · doi:10.48550/arxiv.1303.3997 · Cited by 9,540 · see citing works
McCarthy, D. J., Chen, Y., & Smyth, G. K. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks042 · Cited by 5,195 · see citing works
CellProfiler: image analysis software for identifying and quantifying cell phenotypes
Carpenter, A. E., Jones, T. R., Lamprecht, M. R., Clarke, C., Kang, I. H., Friman, O., Guertin, D. A., Chang, J. H., Lindquist, R. A., Moffat, J., et al. (2006) · Genome biology · doi:10.1186/gb-2006-7-10-r100 · Cited by 5,077 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · see citing works
Self-citationComplement and microglia mediate early synapse loss in Alzheimer mouse models
Hong, S., Beja-Glasser, V. F., Nfonoyim, B. M., Frouin, A., Li, S., Ramakrishnan, S., Merry, K. M., Shi, Q., Rosenthal, A., Barres, B. A., et al. (2016) · Science · doi:10.1126/science.aad8373 · Cited by 3,343 · see citing works
Self-citationThe Classical Complement Cascade Mediates CNS Synapse Elimination
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.036 · Cited by 3,313 · see citing works
Self-citationSynaptic Activity and the Construction of Cortical Circuits
Katz, L. C., & Shatz, C. J. (1996) · Science · doi:10.1126/science.274.5290.1133 · Cited by 3,048 · see citing works
Schizophrenia risk from complex variation of complement component 4
Sekar, A., Bialas, A. R., de Rivera, H., Davis, A., Hammond, T. R., Kamitaki, N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., et al. (2016) · Nature · doi:10.1038/nature16549 · Cited by 2,394 · see citing works
Self-citationDELLY: structural variant discovery by integrated paired-end and split-read analysis
Rausch, T., Zichner, T., Schlattl, A., Stütz, A. M., Beneš, V., & Korbel, J. O. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts378 · Cited by 2,384 · see citing works
Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia
Glantz, L. A., & Lewis, D. A. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.1.65 · Cited by 1,636 · see citing works
DEVELOPMENT OF THE VERTEBRATE NEUROMUSCULAR JUNCTION
Sanes, J. R., & Lichtman, J. W. (1999) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.22.1.389 · Cited by 1,532 · see citing works
McCutcheon, R. A., Reis Marques, T., & Howes, O. D. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2019.3360 · Cited by 1,481 · see citing works
Bourin, M., & Hascoët, M. (2003) · European Journal of Pharmacology · doi:10.1016/s0014-2999(03)01274-3 · Cited by 1,440 · see citing works
Extraordinary neoteny of synaptic spines in the human prefrontal cortex
Petanjek, Z., Judaš, M., Šimić, G., Rašin, M. R., Uylings, H. B. M., Rakic, P., & Kostović, I. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105108108 · Cited by 1,411 · see citing works
Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence?
Feinberg, I. (1982) · Journal of Psychiatric Research · doi:10.1016/0022-3956(82)90038-3 · Cited by 1,395 · see citing works
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
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., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377 · see citing works
Cunningham, F., Achuthan, P., Akanni, W., Allen, J., Amode, M. R., Armean, I. M., Bennett, R., Bhai, J., Billis, K., Boddu, S., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1113 · Cited by 925 · see citing works
Correll, C. U., & Schooler, N. R. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s225643 · Cited by 911 · see citing works
Functional requirement for class I MHC in CNS development and plasticity
Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., & Shatz, C. J. (2000) · Science · doi:10.1126/science.290.5499.2155 · Cited by 828 · see citing works
Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction
Weinhard, L., di Bartolomei, G., Bolasco, G., Machado, P., Schieber, N. L., Neniskyte, U., Exiga, M., Vadisiute, A., Raggioli, A., Schertel, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03566-5 · Cited by 790 · see citing works
Neurocognitive Architecture of Working Memory
Eriksson, J., Vogel, E. K., Lansner, A., Bergström, F., & Nyberg, L. H. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.020 · Cited by 655 · see citing works
Cannon, T. D., Chung, Y., He, G., Sun, D., Jacobson, A., van Erp, T. G. M., McEwen, S., Addington, J., Bearden, C. E., Cadenhead, K., et al. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.023 · Cited by 599 · see citing works
Dendritic spine pathology in schizophrenia
Glausier, J. R., & Lewis, D. A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.044 · Cited by 581 · see citing works
Regulation of Class I MHC Gene Expression in the Developing and Mature CNS by Neural Activity
Corriveau, R. A., Huh, G. S., & Shatz, C. J. (1998) · Neuron · doi:10.1016/s0896-6273(00)80562-0 · Cited by 548 · see citing works
CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development
Lehrman, E. K., Wilton, D. K., Litvina, E. Y., Welsh, C. A., Chang, S. T., Frouin, A., Walker, A. J., Heller, M. D., Umemori, H., Chen, C., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.017 · Cited by 464 · see citing works
Self-citationNeural activity and the dynamics of central nervous system development
Hua, J. Y., & Smith, S. J. (2004) · Nature Neuroscience · doi:10.1038/nn1218 · Cited by 450 · see citing works
Werneburg, S., Jung, J., Kunjamma, R. B., Ha, S.-K., Luciano, N. J., Willis, C. M., Gao, G., Biscola, N. P., Havton, L. A., Crocker, S. J., et al. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.004 · Cited by 440 · see citing works
The structural basis of the multiple forms of human complement component C4
Belt, K., Carroll, M. C., & Porter, R. R. (1984) · Cell · doi:10.1016/0092-8674(84)90040-0 · Cited by 417 · see citing works
Self-citationLarge multiallelic copy number variations in humans
Handsaker, R. E., Doren, V. V., Berman, J. R., Genovese, G., Kashin, S., Boettger, L. M., & McCarroll, S. A. (2015) · Nature Genetics · doi:10.1038/ng.3200 · Cited by 382 · see citing works
Self-citationPrenatal and postnatal development of retinogeniculate and retinocollicular projections in the mouse
Godement, P., Salaün, J., & Imbert, M. (1984) · The Journal of Comparative Neurology · doi:10.1002/cne.902300406 · Cited by 378 · see citing works
Werneburg, S., Jung, J., Kunjamma, R. B., Ha, S., Luciano, N., Willis, C. M., Gao, G., Biscola, N. P., Havton, L., Crocker, S., et al. (2019) · bioRxiv · doi:10.1101/841601 · Cited by 369 · see citing works
Regulation of the B cell response to T-dependent antigens by classical pathway complement
Fischer, M. B., Ma, M., Goerg, S., et al. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.2.549 · Cited by 364 · see citing works
Self-citationCannon, T. D., Thompson, P. M., van Erp, T. G. M., Toga, A. W., Poutanen, V.-P., HUTTUNEN, M. O., Lönnqvist, J. K., Standerskjold-Nordenstam, C.-G., Narr, K. L., Khaledy, M., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052023499 · Cited by 315 · see citing works
Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse
Hooks, B. M., & Chen, C. (2006) · Neuron · doi:10.1016/j.neuron.2006.07.007 · Cited by 311 · see citing works
A comparison of the properties of two classes, C4A and C4B, of the human complement component C4
Law, S. K., Dodds, A. W., & Porter, R. R. (1984) · The EMBO Journal · doi:10.1002/j.1460-2075.1984.tb02052.x · Cited by 303 · see citing works
Complement System in Neural Synapse Elimination in Development and Disease
Présumey, J., Bialas, A. R., & Carroll, M. C. (2017) · Advances in immunology · doi:10.1016/bs.ai.2017.06.004 · Cited by 278 · see citing works
Self-citationInflammatory components in human Alzheimer’s disease and after active amyloid-β42 immunization
Zotova, E., Bharambe, V., Cheaveau, M., Morgan, W., Holmes, C., Harris, S., Neal, J. W., Love, S., Nicoll, J. A. R., & Boche, D. (2013) · Brain · doi:10.1093/brain/awt210 · Cited by 272 · see citing works
Isenman, D. E., & Young, J. R. (1984) · The Journal of Immunology · doi:10.4049/jimmunol.132.6.3019 · Cited by 241 · see citing works
Rabinowitz, S. S., & Gordon, S. (1991) · The Journal of experimental medicine · doi:10.1084/jem.174.4.827 · Cited by 233 · see citing works
Structural and functional composition of the developing retinogeniculate pathway in the mouse
Jaubert-Miazza, L., Green, E., Lo, F., Bui, K., MILLS, J., & Guido, W. (2005) · Visual Neuroscience · doi:10.1017/s0952523805225154 · Cited by 232 · see citing works
Classical MHCI Molecules Regulate Retinogeniculate Refinement and Limit Ocular Dominance Plasticity
Datwani, A., McConnell, M. J., Kanold, P. O., Micheva, K. D., Busse, B., Shamloo, M., Smith, S. J., & Shatz, C. J. (2009) · Neuron · doi:10.1016/j.neuron.2009.10.015 · Cited by 212 · see citing works
Ko, J. (2017) · Frontiers in Neural Circuits · doi:10.3389/fncir.2017.00041 · Cited by 212 · see citing works
Neuronal Pentraxins Mediate Synaptic Refinement in the Developing Visual System
Bjartmar, L., Huberman, A. D., Ullian, E. M., Renteria, R. C., Liu, X., Xu, W., Prezioso, J., Susman, M. W., Stellwagen, D., Stokes, C. C., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4212-05.2006 · Cited by 179 · see citing works
Keuren, M. L. V., Gavrilina, G. B., Filipiak, W. E., Zeidler, M. G., & Saunders, T. L. (2009) · Transgenic Research · doi:10.1007/s11248-009-9271-2 · Cited by 135 · see citing works
Yang, Y., Chung, E. K., Zhou, B., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.5.2734 · Cited by 121 · see citing works
An Engulfment Assay: A Protocol to Assess Interactions Between CNS Phagocytes and Neurons
Schafer, D. P., Lehrman, E. K., Heller, C. T., & Stevens, B. (2014) · Journal of Visualized Experiments · doi:10.3791/51482 · Cited by 108 · see citing works
Self-citationRefinement of the retinogeniculate pathway
Guido, W. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.157115 · Cited by 97 · see citing works
Bochner, D., Sapp, R. W., Steinmetz, J. D., Zhang, S., Lee, H., Djurisic, M. R., Syken, J., Dan, Y., & Shatz, C. J. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3010157 · Cited by 92 · see citing works
Isenman, D. E., & Young, J. R. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.136.7.2542 · Cited by 61 · see citing works
Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia inductionPreprint
Weinhard, L., Neniškytė, U., Bartolomei, G. D., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/190975 · Cited by 52 · see citing works
Macrophage-Derived Complement Component C4 Can Restore Humoral Immunity in C4-Deficient Mice
Gadjeva, M. G., Verschoor, A., Brockman, M. A., Jezak, H., Shen, L. M., Knipe, D. M., & Carroll, M. C. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5489 · Cited by 50 · see citing works
Self-citationFinco, O., Li, S., Cuccia, M., Rosen, F. S., & Carroll, M. C. (1992) · The Journal of Experimental Medicine · doi:10.1084/jem.175.2.537 · Cited by 39 · see citing works
Self-citationNonaka, M., Kimura, H., Yeul, Y. D., Yokoyama, S., Nakayama, K. I., & Takahashi, M. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.20.7883 · Cited by 35 · see citing works
Singh, R. K., Su, J., Brooks, J. M., Terauchi, A., Umemori, H., & Fox, M. A. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00061 · Cited by 35 · see citing works
Koyama, Y., Hattori, T., Nishida, T., Hori, O., & Tohyama, M. (2015) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2015.00052 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Function and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662 · see citing works
Zhou, J., Wade, S. D., Graykowski, D., Xiao, M.-F., Zhao, B., Giannini, L. A. A., Hanson, J. E., van Swieten, J. C., Sheng, M., Worley, P. F., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adf0141 · Cited by 152 · see citing works
Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development
Reynolds, L. M., & Flores, C. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.735625 · Cited by 137 · see citing works
Sex Differences in Neurodevelopmental Disorders: A Key Role for the Immune System
Breach, M. R., & Lenz, K. M. (2022) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2022_308 · Cited by 62 · see citing works
Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer’s disease
Morshed, N., Lee, M. J., Rodriguez, F. H., Lauffenburger, D. A., Mastroeni, D., & White, F. M. (2021) · Nature Aging · doi:10.1038/s43587-021-00071-1 · Cited by 58 · see citing works
Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
Exposito-Alonso, D., & Rico, B. (2022) · Annual Review of Genetics · doi:10.1146/annurev-genet-072820-023642 · Cited by 49 · see citing works
Genes and Pseudogenes: Complexity of the RCCX Locus and Disease
Carrozza, C., Foca, L., De Paolis, E., & Concolino, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.709758 · Cited by 37 · see citing works
Suriano, C. M., Kumar, N., Verpeut, J. L., Ma, J., Jung, C., Dunn, C. E., Carvajal, B. V., Nguyen, A. V., & Boulanger, L. M. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.036 · Cited by 21 · see citing works
- Authors
- Yilmaz, M., Yalcin, E., Presumey, J., Aw, E., Ma, M., Whelan, C. W., Stevens, B., McCarroll, S. A., & Carroll, M. C.
- Affiliations
- Boston Children's Hospital (US)
- Broad Institute (US)
- Corresponding author
- Carroll, Michael C.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2020-12-22
- Volume
- 24
- Issue
- 2
- Pages
- 214-224
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC8086435
- OpenAlex
- W3114419121
- Cited by
- 321
- References
- 57
- Citations by year
- 2026: 42 · 2025: 64 · 2024: 64 · 2023: 63 · 2022: 52 · 2021: 35 · 2012: 1
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (P50MH112491)
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR072965)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- complement C4A, schizophrenia, synaptic pruning, synaptic loss, complement C4B, visual system development, mouse model, behavioral abnormalities, schizophrenia risk genes
- MeSH terms
- Animals, Behavior, Animal, Complement C4, Depression, Female, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Psychomotor Performance, Schizophrenia, Schizophrenic Psychology, Synapses, Synaptosomes, Microglia, Mice, Knockout, Gene Dosage, Dendritic Spines, 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
