CUB and Sushi Multiple Domains 1 (CSMD1) Opposes the Complement Cascade in Neural Tissues
Baum, Matthew L., Daniel K. Wilton, Allie Muthukumar, Rachel G. Fox, Alanna Carey, William Crotty, Nicole Scott-Hewitt, Elizabeth Bien, David A. Sabatini, Toby Lanser, Arnaud Frouin, Frederick Gergits, Bjarte Håvik, Chrysostomi Gialeli, Eugene Nacu, Anna M. Blom, Kevin Eggan, Matthew B. Johnson, Steven A. McCarroll, Beth Stevens
This preprint manuscript describes the complement inhibitory capacity, and loss-of-function synaptic pruning phenotypes of CSMD1, a protein that inhibits C4’s function in the complement cascade and is encoded by a schizophrenia risk locus.
Complement Genes Contribute Sex-Biased Vulnerability in Diverse Disorders
Kamitaki, Nolan, Aswin Sekar, Robert E. Handsaker, Heather de Rivera, Katherine Tooley, David L. Morris, Kimberly E. Taylor, Christopher W Whelan, Philip Tombleson, Loes M Olde Loohuis, Schizophrenia Working Group of the Psychiatric Genomics Consortium; Michael Boehnke, Robert P Kimberly, Kenneth M Kaufman, John B Harley, Carl D Langefeld, Christine E Seidman, Michele T Pato, Carlos N Pato, Roel A Ophoff, Robert R Graham, Lindsey A Criswell, Timothy J Vyse, Steven A McCarroll
This paper elucidates the differential risk profiles arising from C4 locus genetic variation for men and women, and the complex relationships between C4A-related risk for schizophrenia versus autoimmune disorders such as lupus. The McCarroll lab also presents here foundational data on complement component C3 and C4 protein levels in the CSF across the lifespan of healthy adults, demonstrating that sex and age effects, in addition to C4 genotype, are highly significant covariates in any consideration of complement as fluid biomarkers. Finally, this paper also describes a computational method and data resource for imputing C4 genotypes from SNP data, which will be highly useful in a variety of research and translational contexts considering the complex influence of C4 variation on complement expression and disease risk.
Local Externalization of Phosphatidylserine Mediates Developmental Synaptic Pruning by Microglia
Scott-Hewitt, Nicole, Fabio Perrucci, Raffaella Morini, Marco Erreni, Matthew Mahoney, Agata Witkowska, Alanna Carey, Elisa Faggiani, Lisa Theresia Schuetz, Sydney Mason, Matteo Tamborini, Matteo Bizzotto, Lorena Passoni, Fabia Filipello, Reinhard Jahn, Beth Stevens, Michela Matteoli
The EMBO Journal, 2020
This paper describes regulation and consequences of phosphatidylserine exposure on neuronal and synaptic membranes, which may serve to recruit or regulate complement activity at synapses and their downstream phagocytosis by microglia.
Overexpression of Schizophrenia Susceptibility Factor Human Complement C4A Promotes Excessive Synaptic Loss and Behavioral Changes in Mice
Yilmaz, Melis, Esra Yalcin, Jessy Presumey, Ernest Aw, Minghe Ma, Christopher W. Whelan, Beth Stevens, Steven A. McCarroll, and Michael C. Carroll.
Nature Neuroscience, 2020
This paper presents a comprehensive analysis of the impact of human C4A and C4B expression and dosage effects in humanized mouse models. hC4A and hC4B display differences in synaptic tagging and downstream phenotypes, consistent with the differential schizophrenia risk profile of these isotypes. Overexpression of hC4A results in increased synaptic pruning by microglia, altered circuit development, and changes in behavior. These results strongly support a role for neuroimmune mechanisms in prefrontal circuit development and psychiatric vulnerability, and advance the pruning hypothesis of schizophrenia.
Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes
Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJM, Piao X, McCarroll SA, Stevens B
We analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers.
Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, Walker AJ, Heller MD, Umemori H, Chen C, Stevens B
Here, we demonstrate that an innate immune signaling pathway protects synapses from inappropriate removal. The expression patterns of CD47 and its receptor, SIRPα, correlated with peak pruning in the developing retinogeniculate system, and mice lacking these proteins exhibited increased microglial engulfment of retinogeniculate inputs and reduced synapse numbers in the dorsal lateral geniculate nucleus. In addition, CD47 was found to be required for neuronal activity-mediated changes in engulfment, as microglia in CD47 knockout mice failed to display preferential engulfment of less active inputs.
Hammond TR, Robinton D, Stevens B.
Annual Review of Cell and Developmental Biology, 2018
In this review, we discuss the crucial roles that microglia play in shaping the brain – from their influence on neurons and glia within the developing CNS to their roles in synaptic maturation and brain wiring – as well as some of the obstacles to overcome when assessing their contributions to normal brain development. Furthermore, we examine how normal developmental functions of microglia are perturbed or remerge in neurodevelopmental and neurodegenerative disease.
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA.
The results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
Pruning hypothesis comes of age. 29469125
Microglia: Phagocytosing to Clear, Sculpt, and Eliminate. Hong S, Stevens B (2016). Developmental Cell. July 25; 38(2) 126-128. PMID 27459063
Do Glia Drive Synaptic and Cognitive Impairment in Disease? Welsh, C. Chung W-S, Barres BA and Stevens B (2015). Nature Neuroscience. Nov; 18(11):1539-45. doi: 10.1038/nn.4142. PMID 26505565
Microglia: Dynamic Mediators of Synapse Development and Plasticity. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015). Trends in Immunology. Oct 36:10: 605-13 PMID 26431938
Microglial Function in Central Nervous System Development and Plasticity. Schafer DP and Stevens B (2015). Cold Spring Harbor Perspectives in Biology: “GLIA”. Edited by Barres BA, Stevens B, and Freeman, M. Cold Spring Harbor Perspectives in Biology. 2015 Jul 17; 7(10): a020545. PMID 26187728
Phagocytic glial cells: Sculpting synaptic circuits in the developing nervous system. Schafer DP and Stevens B (2013). Current Opinion in Neurobiology. 23(6):1034-40. PMID 24157239
The complement system: an unexpected role in synaptic pruning during development and disease. Steffan, AH, Barres BA and Stevens, B (2012). Annual Review of Neuroscience. 35:369-89. PMID 22715882
Structured Illumination Microscopy for the investigation of synaptic structure and function.Hong S*, Wilton D*, Stevens B & Richardson D (*Equal contribution) (2017). Methods in Molecular Biology; Synapse Development: Methods Mol Biol. 1538; 155-167 PMID 27943190
An Engulfment Assay: A Protocol to Assess Interactions between CNS Phagocytes and Neuron. Schafer D., Lehrman EK, Heller CT and Stevens B (2014). Journal of Visualized Experiments. Jun 8; (88) PMID 24962472
An Ultrahigh-Affinity Complement C4b-Specific Nanobody Inhibits In Vivo Assembly of the Classical Pathway Proconvertase. Zarantonello, Alessandra, Jessy Presumey, Léa Simoni, Esra Yalcin, Rachel Fox, Annette Hansen, Heidi Gytz Olesen, Steffen Thiel, Matthew B Johnson, Beth Stevens, Nick Stub Laursen, Michael C Carroll, Gregers R Andersen (2020). Journal of Immunology. Sep 15;205(6):1678-1694. PMID 32769120
Ocular Dominance Plasticity in Binocular Primary Visual Cortex Does Not Require C1q. Welsh, Christina A., Céleste-Élise Stephany, Richard W. Sapp, and Beth Stevens. (2020). The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. Jan 22;40(4):769-783.PMID 31801811
Complement C4A Regulates Autoreactive B Cells in Murine Lupus. Simoni, Léa, Jessy Presumey, Cees E. van der Poel, Carlos Castrillon, Sarah E. Chang, Paul J. Utz, and Michael C. Carroll. (2020). Cell Reports. Nov 3;33(5):108330. PMID 33147456
A Complement C3-Specific Nanobody for Modulation of the Alternative Cascade Identifies the C-Terminal Domain of C3b as Functional in C5 Convertase Activity. Pedersen, Henrik, Rasmus K. Jensen, Jens Magnus B. Jensen, Rachel Fox, Dennis V. Pedersen, Heidi G. Olesen, Annette G. Hansen, Dorte Christiansen, Sofia M M Mazarakis, Neal Lojek, Pernille Hansen, Trine A F Gadeberg, Alessandra Zarantonello, Nick S Laursen, Tom Eirik Mollnes, Matthew B Johnson, Beth Stevens, Steffen Thiel, Gregers R Andersen (2020). Journal of Immunology. Oct 15;205(8):2287-2300. PMID 32938727
Complement and Microglia Mediate Early Synapse Loss in Alzheimer’s Mouse Models. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016). Science. May 6; 352(6286):712-6. PMID 27033548
Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA (2017). Science Translational Medicine. May 31;9(392). PMID 28566429
A complement-microglial axis drives synapse loss during virus-induced memory impairment. Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B, Soung A, Yu J, Perez-Torres C, Frouin A, Wilton DK, Funk K, DeMasters BK, Jiang X, Bowen JR, Mennerick S, Robinson JK, Garbow JR, Tyler KL, Suthar MS, Schmidt RE, Stevens B, Klein RS. (2016). Nature. Jun 23;534(7608):538-43. PMID 27337340
TGF-β Signaling Regulates Neuronal C1q Expression and Developmental Synaptic Refinement. Bialas A and Stevens, B (2013). Nature Neuroscience. 16(12):1773-82. PMID 24162655
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement- dependent manner. Schafer D, Lehrman E. Kautzman A, Koyama, R, Mardinly A, Greenberg ME, Barres BA, and Stevens, B (2012). Neuron. 74; 1-15. PMID 22632727
Enhanced synaptic connectivity and epilepsy in C1q knockout mice.Chu Y, Ji X, Parada I, Pesic A, Stevens B, Barres BA and Prince DA (2010). PNAS. 107 (17) 7975-80. PMID 20375278
The classical complement cascade mediates developmental CNS synapse elimination. Stevens B, Allen NJ, Christopherson KS, Vazquez LE, Nouri N, Howell GR, Micheva KD, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John, SWM, Barres, BA (2007). Cell. 131:1164-78. PMID 18083105