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Research Overview

We are interested in interactions between the two fundamental cell types of the nervous system, neurons and glia. My laboratory seeks to understand how neuron-glia communication facilitates the formation, elimination and plasticity of synapses—the points of communication between neurons—during both healthy development and disease.

We focus on the role of neuron-glia and neural-immune interactions in the patterning of neural circuits. We and our collaborators have identified an unexpected role for glia and components of the innate immune system in synaptic pruning. We find that astrocytes induce neuronal expression of complement C1q, the initiating protein of the classical complement cascade (which tags unwanted cells and debris for elimination in the immune system). C1q and downstream complement proteins target synapses and are required for synapse elimination in the developing visual system. Importantly, we find that C1q becomes aberrantly upregulated and is relocalized to synapses in the early stages of glaucoma, suggesting that a similar elimination mechanism may be in place during both healthy central-nervous-system (CNS) development and neurodegenerative diseases.

Our ongoing studies are directed toward defining the cellular and molecular mechanisms underlying synapse elimination during health and disease, with emphasis on the role of complement in this process. In addition to our interest in CNS neurodegenerative diseases, we are currently collaborating with other laboratories to further probe the potential link between complement proteins and synapse loss in the pathogenesis of epilepsy and neurodevelopmental disorders.

A microglial cell labeled with green fluorescent protein (GFP). The microglial processes are closely positioned and interacting with retinal ganglion cell inputs (red and turquoise) in the dorsal lateral geniculate nucleus of the thalamus. Image was acquired from a postnatal day 30 mouse.

One current goal is to understand how synapses in the CNS are selectively targeted for elimination. Why does one synapse get eliminated while a nearby synapse stays intact? Our recent findings suggest that microglia—the immune cells of the CNS—may play an important role in the elimination process.

We are also interested in identifying the activity-dependent and molecular cues that regulate expression of complement proteins in the developing and diseased brain, and in determining the specific synaptic sites at which these proteins act. How might glial-derived signals impact other developmental processes, such as synaptogenesis and the myelination of axons? We employ a combination of live imaging, molecular, biochemical and neuroanatomical approaches to address these and other mechanistic questions.

About Beth Stevens

Beth Stevens received her PhD in Neuroscience in 2003 from the University of Maryland, College Park and completed her postdoctoral fellowship at the Stanford University School of Medicine in 2008. She is a recipient of the 2008 Smith Family Award for Excellence in Biomedical Research, a 2010 Dana Foundation Award (Brain and Immunoimaging) and a 2010 Ellison Medical Foundation New Scholar in Aging award.  Dr. Stevens received the Presidential Early Career Award for Scientists and Engineers in 2012.  In 2015, she was selected for a MacArthur Foundation Fellowship.

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Researcher Areas

  • Neuron-Glia Signaling
  • Synapse Development
  • Plasticity

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PUBLICATIONS

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  1. Giera S, Luo R, Ying Y, Ackerman SD, Jeong SJ, Stoveken HM, Folts CJ, Welsh CA, Tall GG, Stevens B, Monk KR, Piao X. Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. Elife. 2018 May 29; 7. View abstract
  2. Stevens B, Schafer DP. Roles of microglia in nervous system development, plasticity, and disease. Dev Neurobiol. 2018 Jun; 78(6):559-560. View abstract
  3. Lloyd AC, Stevens B. Editorial overview: Glial biology. Curr Opin Neurobiol. 2017 Dec; 47:iv-vi. View abstract
  4. Hong S, Stevens B. TREM2: Keeping Microglia Fit during Good Times and Bad. Cell Metab. 2017 Oct 03; 26(4):590-591. View abstract
  5. Schecter RW, Maher EE, Welsh CA, Stevens B, Erisir A, Bear MF. Experience-Dependent Synaptic Plasticity in V1 Occurs without Microglial CX3CR1. J Neurosci. 2017 Nov 01; 37(44):10541-10553. View abstract
  6. Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017 Sep 08; 23(9):1018-1027. View abstract
  7. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017 05 31; 9(392). View abstract
  8. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 01 26; 541(7638):481-487. View abstract
  9. Hong S, Wilton DK, Stevens B, Richardson DS. Structured Illumination Microscopy for the Investigation of Synaptic Structure and Function. Methods Mol Biol. 2017; 1538:155-167. View abstract
  10. Hammond TR, Stevens B. Increasing the neurological-disease toolbox using iPSC-derived microglia. Nat Med. 2016 11 08; 22(11):1206-1207. View abstract
  11. Loh KH, Stawski PS, Draycott AS, Udeshi ND, Lehrman EK, Wilton DK, Svinkina T, Deerinck TJ, Ellisman MH, Stevens B, Carr SA, Ting AY. Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts. Cell. 2016 Aug 25; 166(5):1295-1307.e21. View abstract
  12. Schafer DP, Heller CT, Gunner G, Heller M, Gordon C, Hammond T, Wolf Y, Jung S, Stevens B. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife. 2016 07 26; 5. View abstract
  13. Hong S, Stevens B. Microglia: Phagocytosing to Clear, Sculpt, and Eliminate. Dev Cell. 2016 07 25; 38(2):126-8. View abstract
  14. 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. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016 06 23; 534(7608):538-43. View abstract
  15. 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. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 06; 352(6286):712-716. View abstract
  16. All You Need Is Mentorship. Cell. 2016 Mar 10; 164(6):1092-1093. View abstract
  17. Stevens B, Muthukumar AK. Cellular neuroscience. Differences among astrocytes. Science. 2016 Feb 19; 351(6275):813. View abstract
  18. 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, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4. Nature. 2016 Feb 11; 530(7589):177-83. View abstract
  19. Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol. 2016 Feb; 36:128-34. View abstract
  20. Chung WS, Welsh CA, Barres BA, Stevens B. Do glia drive synaptic and cognitive impairment in disease? Nat Neurosci. 2015 Nov; 18(11):1539-1545. View abstract
  21. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol. 2015 Oct; 36(10):605-613. View abstract
  22. Shi Q, Colodner KJ, Matousek SB, Merry K, Hong S, Kenison JE, Frost JL, Le KX, Li S, Dodart JC, Caldarone BJ, Stevens B, Lemere CA. Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline. J Neurosci. 2015 Sep 23; 35(38):13029-42. View abstract
  23. Dissing-Olesen L, Hong S, Stevens B. New Brain Lymphatic Vessels Drain Old Concepts. EBioMedicine. 2015 Aug; 2(8):776-7. View abstract
  24. Schafer DP, Stevens B. Microglia Function in Central Nervous System Development and Plasticity. Cold Spring Harb Perspect Biol. 2015 Jul 17; 7(10):a020545. View abstract
  25. Lehrman EK, Stevens B. Shedding light on glioma growth. Cell. 2015 May 07; 161(4):704-6. View abstract
  26. Schafer DP, Stevens B. Brains, Blood, and Guts: MeCP2 Regulates Microglia, Monocytes, and Peripheral Macrophages. Immunity. 2015 Apr 21; 42(4):600-2. View abstract
  27. Giera S, Deng Y, Luo R, Ackerman SD, Mogha A, Monk KR, Ying Y, Jeong SJ, Makinodan M, Bialas AR, Chang BS, Stevens B, Corfas G, Piao X. The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat Commun. 2015 Jan 21; 6:6121. View abstract
  28. Risher WC, Patel S, Kim IH, Uezu A, Bhagat S, Wilton DK, Pilaz LJ, Singh Alvarado J, Calhan OY, Silver DL, Stevens B, Calakos N, Soderling SH, Eroglu C. Astrocytes refine cortical connectivity at dendritic spines. Elife. 2014 Dec 17; 3. View abstract
  29. Bilimoria PM, Stevens B. Microglia function during brain development: New insights from animal models. Brain Res. 2015 Aug 18; 1617:7-17. View abstract
  30. Schafer DP, Lehrman EK, Heller CT, Stevens B. An engulfment assay: a protocol to assess interactions between CNS phagocytes and neurons. J Vis Exp. 2014 Jun 08; (88). View abstract
  31. Wu LJ, Stevens B, Duan S, MacVicar BA. Microglia in neuronal circuits. Neural Plast. 2013; 2013:586426. View abstract
  32. Bialas AR, Stevens B. TGF-ß signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013 Dec; 16(12):1773-82. View abstract
  33. Schafer DP, Stevens B. Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr Opin Neurobiol. 2013 Dec; 23(6):1034-40. View abstract
  34. Bialas AR, Stevens B. Glia: regulating synaptogenesis from multiple directions. Curr Biol. 2012 Oct 09; 22(19):R833-5. View abstract
  35. Schafer DP, Lehrman EK, Stevens B. The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS. Glia. 2013 Jan; 61(1):24-36. View abstract
  36. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012 May 24; 74(4):691-705. View abstract
  37. Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012; 35:369-89. View abstract
  38. Tremblay MÈ, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci. 2011 Nov 09; 31(45):16064-9. View abstract
  39. Ransohoff RM, Stevens B. Neuroscience. How many cell types does it take to wire a brain? Science. 2011 Sep 09; 333(6048):1391-2. View abstract
  40. Blank M, Fuerst PG, Stevens B, Nouri N, Kirkby L, Warrier D, Barres BA, Feller MB, Huberman AD, Burgess RW, Garner CC. The Down syndrome critical region regulates retinogeniculate refinement. J Neurosci. 2011 Apr 13; 31(15):5764-76. View abstract
  41. Håvik B, Le Hellard S, Rietschel M, Lybæk H, Djurovic S, Mattheisen M, Mühleisen TW, Degenhardt F, Priebe L, Maier W, Breuer R, Schulze TG, Agartz I, Melle I, Hansen T, Bramham CR, Nöthen MM, Stevens B, Werge T, Andreassen OA, Cichon S, Steen VM. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry. 2011 Jul 01; 70(1):35-42. View abstract
  42. Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I, Kneeland SC, Barbay JM, King BL, Marchant JK, Hibbs M, Stevens B, Barres BA, Clark AF, Libby RT, John SW. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest. 2011 Apr; 121(4):1429-44. View abstract
  43. Chu Y, Jin X, Parada I, Pesic A, Stevens B, Barres B, Prince DA. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc Natl Acad Sci U S A. 2010 Apr 27; 107(17):7975-80. View abstract
  44. Schafer DP, Stevens B. Synapse elimination during development and disease: immune molecules take centre stage. Biochem Soc Trans. 2010 Apr; 38(2):476-81. View abstract
  45. Rosen AM, Stevens B. The role of the classical complement cascade in synapse loss during development and glaucoma. Adv Exp Med Biol. 2010; 703:75-93. View abstract
  46. Stevens B. Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neurosignals. 2008; 16(4):278-88. View abstract
  47. Chen Y, Stevens B, Chang J, Milbrandt J, Barres BA, Hell JW. NS21: re-defined and modified supplement B27 for neuronal cultures. J Neurosci Methods. 2008 Jun 30; 171(2):239-47. View abstract
  48. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA. The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec 14; 131(6):1164-78. View abstract
  49. Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL, Fields RD. Astrocytes promote myelination in response to electrical impulses. Neuron. 2006 Mar 16; 49(6):823-32. View abstract
  50. Stevens B. Cross-talk between growth factor and purinergic signalling regulates Schwann cell proliferation. Novartis Found Symp. 2006; 276:162-75; discussion 175-80, 233-7, 275-81. View abstract
  51. Stevens B. Glia: much more than the neuron's side-kick. Curr Biol. 2003 Jun 17; 13(12):R469-72. View abstract
  52. Stevens B, Porta S, Haak LL, Gallo V, Fields RD. Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials. Neuron. 2002 Dec 05; 36(5):855-68. View abstract