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    Dorothy P Schafer PhD

    TitleAssistant Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurobiology
    AddressUniversity of Massachusetts Medical School
    55 Lake Ave North
    Worcester MA 01605
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentImmunology and Microbiology Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Biography 
        awards and honors
        NARSAD2017 - 2019Young Investigator Grant
        Charles H. Hood Foundation2016 - 2018Child Health Research Award
        Worcester Foundation2016 - 2017Biomedical Research Award
        NIMH2014 - 2018K99/R00 Career Transition Award
        Nancy Lurie Marks2012 - 2013Postdoctoral Fellowship Award
        Harvard University2010 - 2011Bok Center distinction for excellence in teaching
        NINDS2010 - 2012NRSA F32 Postdoctoral Fellowship
        American Society for Neurochemistry2010 - 2011Marian Keyes Award for outstanding graduate work
        University of Connecticut Health Center2007 - 2007Lepow Award for outstanding graduate work
        Overview 
        Narrative

        Biography

        Dori Schafer earned her Bachelor’s degree in Neuroscience and Behaviour from Mount Holyoke College in 2001. She attended graduate school at the University of Connecticut Health Center in Matthew Rasband’s lab where she used rodent models to study neuron-glia interactions regulating assembly and maintenance of functional, polarized domains along the axon, nodes of Ranvier and axon initial segments. Upon completion of her PhD in 2008, she began her postdoctoral training in the laboratory of Beth Stevens at Boston Children’s Hospital. While in the Stevens lab (2008-2014), she studied the role of microglia, the resident CNS myeloid-derived cell, in mammalian synapse development and plasticity.  She was recently hired in 2015 as a tenure-track Assistant Professor in the Department of Neurobiology at The University of Massachusetts Medical School. Her laboratory utilizes a combination of molecular biology and high resolution imaging to understand how neurons and glia communicate with one another to regulating synapse development and plasticity.

        Neuron-Glia Interactions Regulating Synaptic Circuit Development and Plasticity

        The primary focus of our research is to understand the role of glial cells in synapse development and plasticity in the healthy and diseased nervous system. To achieve and maintain the precise synaptic connectivity characteristic of the mature organism, synapses must be plastic. This is particularly true in the developing nervous system where, during critical periods of heightened plasticity, spontaneous activity and experience drive synapse remodeling. The importance of these processes are further emphasized in neurodevelopmental and neuropsychiatric disorders, where it is becoming clear that critical period plasticity is particularly vulnerable to disruption.

         

        It is also emerging that glia are far more than “brain glue,” playing active roles in shaping and maintaining the nervous system. Recently, we demonstrated a surprising role for microglia, the resident CNS immune cells and professional phagocytes, in the elimination of excess synapses that form in the developing mammalian visual system. Specifically, we showed that microglia phagocytose synapses in the developing brain in an activity-dependent manner. Genetic or Pharmacological disruption of microglial phagocytic signaling resulted in sustained deficits in brain wiring. However, several fundamental questions remain. How do microglia, as well as other glial cell types, respond on a cellular and molecular level to changes in synaptic activity? How do these responses ultimately translate to development and/or function of synaptic circuits? How do glia contribute to abnormal synaptic circuit development associated with neurodevelopmental and neuropsychiatric diseases (e.g., autism, schizophrenia, etc.)? To address these questions, the lab has developed novel strategies to image glia-synaptic circuit interactions by 2-photon in vivo live imaging in awake, behaving mice. In addition, we have developed techniques to dissect glia-specific molecular mechanisms underlying synaptic plasticity.

         
        1. Investigating Glial Responses to Changes in Sensory Experience in Real Time

        Sensory experience is known to drive synapse remodeling throughout the CNS, particularly during critical periods in development. The developing mammalian barrel cortex and visual cortex are classic examples. We have developed strategies to simultaneously visualize glial cells and specific synaptic circuits known to undergo experience-dependent remodeling in the mouse barrel and visual cortices of awake, behaving mice. In addition, we aim to extend these studies to image responses of other glial cell populations, including myelinating oligodendrocytes and astrocytes, to changes in sensory experience.

        1. Dissecting the molecular mechanisms underlying glial responses to sensory experience

        Glia are known to respond to changes in neural activity, but molecular mechanisms underlying these responses are just beginning to be deciphered. Projects in the lab are designed to identify glia-specific molecules that change in response to changes in neural activity and understand how these genes regulate glial cell biology. To begin, we have now identified several microglia-specific genes that change following manipulation of visual sensory experience.

        1. Understanding the functional consequences of glia-synapse interactions in health and disease

        The functional significance of glial responses to changes in activity and interactions with synapses are still relatively unknown. Beginning with microglia, we are using cell-specific genetic approaches to understand how these cell types contribute to the structure and overall function of synaptic circuits. Furthermore, it is now appreciated that abnormalities in synaptic connectivity and glial cells are hallmarks of several neurodevelopmental and neuropsychiatric disorders. Thus, ongoing projects in the lab are also aimed at understanding how CNS glial cells contribute to this abnormal brain circuitry.



        Rotation Projects

        There are a variety of rotation projects that use a variety of imaging and biochemical techniques to assess glial function in the CNS. The main projects are highlighted below.

        1. Assessing glial responses to changes in neural activity by in vitro and in vivo live imaging.

        2. Identifying molecular mechanisms underlying activity-dependent changes in glial cells.

        3. Assessing structural and functional changes in brain wiring in response to manipulation of glial cell function.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. 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; 5.
          View in: PubMed
        2. Frost JL, Schafer DP. Microglia: Architects of the Developing Nervous System. Trends Cell Biol. 2016 Aug; 26(8):587-97.
          View in: PubMed
        3. Schafer DP, Stevens B. Microglia Function in Central Nervous System Development and Plasticity. Cold Spring Harb Perspect Biol. 2015; 7(10).
          View in: PubMed
        4. Schafer DP, Stevens B. Brains, Blood, and Guts: MeCP2 Regulates Microglia, Monocytes, and Peripheral Macrophages. Immunity. 2015 Apr 21; 42(4):600-2.
          View in: PubMed
        5. Goldey GJ, Roumis DK, Glickfeld LL, Kerlin AM, Reid RC, Bonin V, Schafer DP, Andermann ML. Removable cranial windows for long-term imaging in awake mice. Nat Protoc. 2014 Nov; 9(11):2515-38.
          View in: PubMed
        6. 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; (88).
          View in: PubMed
        7. 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 in: PubMed
        8. 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 in: PubMed
        9. 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 in: PubMed
        10. Susuki K, Yuki N, Schafer DP, Hirata K, Zhang G, Funakoshi K, Rasband MN. Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012 Jan; 233(1):534-42.
          View in: PubMed
        11. 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 in: PubMed
        12. Schafer DP, Jha S, Liu F, Akella T, McCullough LD, Rasband MN. Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. J Neurosci. 2009 Oct 21; 29(42):13242-54.
          View in: PubMed
        13. Liu F, Schafer DP, McCullough LD. TTC, fluoro-Jade B and NeuN staining confirm evolving phases of infarction induced by middle cerebral artery occlusion. J Neurosci Methods. 2009 Apr 30; 179(1):1-8.
          View in: PubMed
        14. Schafer DP, Rasband MN. Glial regulation of the axonal membrane at nodes of Ranvier. Curr Opin Neurobiol. 2006 Oct; 16(5):508-14.
          View in: PubMed
        15. Ogawa Y, Schafer DP, Horresh I, Bar V, Hales K, Yang Y, Susuki K, Peles E, Stankewich MC, Rasband MN. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. J Neurosci. 2006 May 10; 26(19):5230-9.
          View in: PubMed
        16. Schafer DP, Custer AW, Shrager P, Rasband MN. Early events in node of Ranvier formation during myelination and remyelination in the PNS. Neuron Glia Biol. 2006 May; 2(2):69-79.
          View in: PubMed
        17. Schafer DP, Bansal R, Hedstrom KL, Pfeiffer SE, Rasband MN. Does paranode formation and maintenance require partitioning of neurofascin 155 into lipid rafts? J Neurosci. 2004 Mar 31; 24(13):3176-85.
          View in: PubMed
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