ABOUT THE RESEARCHER

OVERVIEW

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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.

BACKGROUND

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.

PUBLICATIONS

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  1. The complement cascade repurposed in the brain. Nat Rev Immunol. 2021 Oct; 21(10):624-625. View abstract
  2. Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve. J Neurosci. 2021 Oct 13; 41(41):8508-8531. View abstract
  3. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell. 2021 Jul 22; 184(15):4048-4063.e32. View abstract
  4. A map of transcriptional heterogeneity and regulatory variation in human microglia. Nat Genet. 2021 06; 53(6):861-868. View abstract
  5. A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2021 03 30; 118(13). View abstract
  6. Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nat Neurosci. 2021 02; 24(2):214-224. View abstract
  7. A Complement C3-Specific Nanobody for Modulation of the Alternative Cascade Identifies the C-Terminal Domain of C3b as Functional in C5 Convertase Activity. J Immunol. 2020 10 15; 205(8):2287-2300. View abstract
  8. Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism. Neuron. 2020 11 11; 108(3):451-468.e9. View abstract
  9. Microglia and Astrocytes in Disease: Dynamic Duo or Partners in Crime? Trends Immunol. 2020 09; 41(9):820-835. View abstract
  10. An Ultrahigh-Affinity Complement C4b-Specific Nanobody Inhibits In Vivo Assembly of the Classical Pathway Proconvertase. J Immunol. 2020 09 15; 205(6):1678-1694. View abstract
  11. Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. EMBO J. 2020 08 17; 39(16):e105380. View abstract
  12. The contribution of glial cells to Huntington's disease pathogenesis. Neurobiol Dis. 2020 09; 143:104963. View abstract
  13. A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. EMBO J. 2020 08 17; 39(16):e104136. View abstract
  14. Microglial depletion disrupts normal functional development of adult-born neurons in the olfactory bulb. Elife. 2020 03 09; 9. View abstract
  15. Ocular Dominance Plasticity in Binocular Primary Visual Cortex Does Not Require C1q. J Neurosci. 2020 01 22; 40(4):769-783. View abstract
  16. Neuron-Glia Signaling in Synapse Elimination. Annu Rev Neurosci. 2019 07 08; 42:107-127. View abstract
  17. Nanoscale Surveillance of the Brain by Microglia via cAMP-Regulated Filopodia. Cell Rep. 2019 06 04; 27(10):2895-2908.e4. View abstract
  18. Immune Signaling in Neurodegeneration. Immunity. 2019 04 16; 50(4):955-974. View abstract
  19. Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity. 2019 01 15; 50(1):253-271.e6. View abstract
  20. CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron. 2018 10 10; 100(1):120-134.e6. View abstract
  21. Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J Exp Med. 2018 10 01; 215(10):2554-2566. View abstract
  22. Microglia and the Brain: Complementary Partners in Development and Disease. Annu Rev Cell Dev Biol. 2018 10 06; 34:523-544. View abstract
  23. A Milieu Molecule for TGF-ß Required for Microglia Function in the Nervous System. Cell. 2018 06 28; 174(1):156-171.e16. View abstract
  24. Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. Elife. 2018 05 29; 7. View abstract
  25. Roles of microglia in nervous system development, plasticity, and disease. Dev Neurobiol. 2018 Jun; 78(6):559-560. View abstract
  26. Pruning hypothesis comes of age. Nature. 2018 02 22; 554(7693):438-439. View abstract
  27. Pruning hypothesis comes of age. Nature. 2018 Feb; 554(7693):438-439. View abstract
  28. Editorial overview: Glial biology. Curr Opin Neurobiol. 2017 12; 47:iv-vi. View abstract
  29. TREM2: Keeping Microglia Fit during Good Times and Bad. Cell Metab. 2017 Oct 03; 26(4):590-591. View abstract
  30. Experience-Dependent Synaptic Plasticity in V1 Occurs without Microglial CX3CR1. J Neurosci. 2017 11 01; 37(44):10541-10553. View abstract
  31. Microglia emerge as central players in brain disease. Nat Med. 2017 Sep 08; 23(9):1018-1027. View abstract
  32. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med. 2017 05 31; 9(392). View abstract
  33. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 01 26; 541(7638):481-487. View abstract
  34. Structured Illumination Microscopy for the Investigation of Synaptic Structure and Function. Methods Mol Biol. 2017; 1538:155-167. View abstract
  35. Increasing the neurological-disease toolbox using iPSC-derived microglia. Nat Med. 2016 11 08; 22(11):1206-1207. View abstract
  36. Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts. Cell. 2016 Aug 25; 166(5):1295-1307.e21. View abstract
  37. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife. 2016 07 26; 5. View abstract
  38. Microglia: Phagocytosing to Clear, Sculpt, and Eliminate. Dev Cell. 2016 07 25; 38(2):126-8. View abstract
  39. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016 06 23; 534(7608):538-43. View abstract
  40. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 06; 352(6286):712-716. View abstract
  41. All You Need Is Mentorship. Cell. 2016 Mar 10; 164(6):1092-1093. View abstract
  42. Cellular neuroscience. Differences among astrocytes. Science. 2016 Feb 19; 351(6275):813. View abstract
  43. Schizophrenia risk from complex variation of complement component 4. Nature. 2016 Feb 11; 530(7589):177-83. View abstract
  44. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol. 2016 Feb; 36:128-34. View abstract
  45. Do glia drive synaptic and cognitive impairment in disease? Nat Neurosci. 2015 Nov; 18(11):1539-1545. View abstract
  46. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol. 2015 Oct; 36(10):605-613. View abstract
  47. Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline. J Neurosci. 2015 Sep 23; 35(38):13029-42. View abstract
  48. New Brain Lymphatic Vessels Drain Old Concepts. EBioMedicine. 2015 Aug; 2(8):776-7. View abstract
  49. Microglia Function in Central Nervous System Development and Plasticity. Cold Spring Harb Perspect Biol. 2015 Jul 17; 7(10):a020545. View abstract
  50. Shedding light on glioma growth. Cell. 2015 May 07; 161(4):704-6. View abstract
  51. Brains, Blood, and Guts: MeCP2 Regulates Microglia, Monocytes, and Peripheral Macrophages. Immunity. 2015 Apr 21; 42(4):600-2. View abstract
  52. The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat Commun. 2015 Jan 21; 6:6121. View abstract
  53. Astrocytes refine cortical connectivity at dendritic spines. Elife. 2014 Dec 17; 3. View abstract
  54. Microglia function during brain development: New insights from animal models. Brain Res. 2015 Aug 18; 1617:7-17. View abstract
  55. An engulfment assay: a protocol to assess interactions between CNS phagocytes and neurons. J Vis Exp. 2014 Jun 08; (88). View abstract
  56. Microglia in neuronal circuits. Neural Plast. 2013; 2013:586426. View abstract
  57. TGF-ß signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013 Dec; 16(12):1773-82. View abstract
  58. Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr Opin Neurobiol. 2013 Dec; 23(6):1034-40. View abstract
  59. Glia: regulating synaptogenesis from multiple directions. Curr Biol. 2012 Oct 09; 22(19):R833-5. View abstract
  60. The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS. Glia. 2013 Jan; 61(1):24-36. View abstract
  61. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012 May 24; 74(4):691-705. View abstract
  62. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012; 35:369-89. View abstract
  63. The role of microglia in the healthy brain. J Neurosci. 2011 Nov 09; 31(45):16064-9. View abstract
  64. Neuroscience. How many cell types does it take to wire a brain? Science. 2011 Sep 09; 333(6048):1391-2. View abstract
  65. The Down syndrome critical region regulates retinogeniculate refinement. J Neurosci. 2011 Apr 13; 31(15):5764-76. View abstract
  66. The complement control-related genes CSMD1 and CSMD2 associate to schizophrenia. Biol Psychiatry. 2011 Jul 01; 70(1):35-42. View abstract
  67. 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
  68. 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
  69. Synapse elimination during development and disease: immune molecules take centre stage. Biochem Soc Trans. 2010 Apr; 38(2):476-81. View abstract
  70. The role of the classical complement cascade in synapse loss during development and glaucoma. Adv Exp Med Biol. 2010; 703:75-93. View abstract
  71. The complement cascade: Yin-Yang in neuroinflammation--neuro-protection and -degeneration. J Neurochem. 2008 Dec; 107(5):1169-87. View abstract
  72. Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neurosignals. 2008; 16(4):278-88. View abstract
  73. NS21: re-defined and modified supplement B27 for neuronal cultures. J Neurosci Methods. 2008 Jun 30; 171(2):239-47. View abstract
  74. The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec 14; 131(6):1164-78. View abstract
  75. Astrocytes promote myelination in response to electrical impulses. Neuron. 2006 Mar 16; 49(6):823-32. View abstract
  76. 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
  77. Glia: much more than the neuron's side-kick. Curr Biol. 2003 Jun 17; 13(12):R469-72. View abstract
  78. 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