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.
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
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