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The Gill Center for Biomolecular Science

Gill Seminars

Previous Speakers

Upcoming Speakers

September 12, 2016
Hugo Bellen, D.V.M., Ph.D.
Howard Hughes Medical Institute, Baylor College of Medicine

Seminar will take place at 3:30 p.m. in the Indiana Memorial Union, Whittenberger Auditorium
during the 2016 Gill Symposium

Title: The Role of Mitochondria, Glia, and Lipid Droplets in the Demise of Neurons

Abstract: An increase in lipid droplets (LD) has been implicated in some metabolic disorders but their role in neurodegeneration is ill defined. We show that several genes that affect mitochondrial function lead to an accumulation of LD in glia prior to or at the onset of neurodegeneration in Drosophila. This LD accumulation is caused by increased reactive oxygen species (ROS), which promotes c-Jun-N-terminal Kinase (JNK) and Sterol Regulatory Element Binding Protein (SREBP) activity, and neuronal activation of this pathway is sufficient to cause glial LD accumulation. LD accumulation can be reduced by lowering ROS, JNK, or SREBP levels, or by overexpressing lipases. These manipulations significantly delay the onset of neurodegeneration. Furthermore, a similar pathway leads to glial LD accumulation in Ndufs4 mutant mice, suggesting that LD accumulation following mitochondrial dysfunction is an evolutionarily conserved phenomenon. Our studies show that increased ROS leads to LD accumulation in glia, and that preventing LD accumulation delays neurodegeneration. 

Through a candidate gene screen to search for proteins that are involved in transporting lipids from neuron to glia, we identified several proteins. We used flies that constitutively expressed a mitochondrial RNAi against a subunit of complex I (ND42) to induce ROS in photoreceptors and LD in glia. By reducing the expression levels of various genes in neuron and glia using RNAi we identified suppressors of the LD accumulation phenotype. We identified two major groups of proteins that are involved in lipid transport. Indeed, loss of some soluble carrier transporters (SLCs) and apolipoproteins strongly suppress LD accumulation. This has allowed us to establish a molecular model for the transport of lipids between neurons and glia.

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September 12, 2016
Beth Stevens, Ph.D.

FM Kirby Neurobiology Center
Boston Children's Hospital
Harvard Medical School
Broad Institute

Seminar will take place at 11:40 a.m. in the Indiana Memorial Union, Whittenberger Auditorium
during the 2016 Gill Symposium.

Title: Immune Mechanisms of Synapse Loss in Health and Disease

Abstract: One of the major unsolved mysteries in neuroscience is how synapses are eliminated in the healthy and diseased brain. During development, neural circuitry undergoes a remodeling process in which excess synapses are eliminated and the remaining synapses are strengthened. This pruning process is required for precise brain wiring; however the mechanisms that drive the elimination of specific synapses in the brain remain unclear. Emerging evidence from several model systems implicate molecules traditionally associated with the adaptive and innate immune system. For example, recent work from our laboratory revealed a key role for microglia and molecules traditionally associated the classical complement cascade in developmental synaptic pruning.  Our recent studies support a model in which ‘weaker’ or less active synapses in the developing brain are targeted by complement proteins (C1q, C3) and then eliminated by phagocytic microglia that express receptors for complement and other immune molecules. These findings raise the question of how microglia differentiate the synapses or axons to prune from those to leave intact. Microglia-mediated synaptic refinement appears to depend on a careful balance of “eat me”  (ie. complement) and a group of novel immune- related protective signals.
An early hallmark of many neurodegenerative diseases (NDDs) is a progressive, region-specific degeneration of synapses.  Our recent work suggest that aberrant activation of some of these normal immune –related pruning pathways mediate early synapse loss in neurodegenerative diseases (NDDs), including Alzheimer’s Disease (AD) and Huntington’s disease (HD). Thus, understanding how these immune mechanisms drive developmental pruning may provide novel insight into how to protect synapses in NDDS and other disorders of synaptic dysfunction, including autism and schizophrenia.

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September 12, 2016
Nicola Allen, Ph.D.

Salk Institute for Biological Studies

Seminar will take place at 9:10 a.m. in the Indiana Memorial Union, Whittenberger Auditorium
during the 2016 Gill Symposium.

Title: Astrocyte Regulation of Neuronal Glutamate Receptors

Abstract: Neuronal synapses are essential points of information transfer within neuronal circuits, and the correct formation and maturation of synapses is necessary for the brain to function throughout life. Astrocytes are the most abundant cell type in the brain, and many synapses have an astrocyte process associated with them. Astrocytes secrete factors that regulate the formation of excitatory glutamatergic synapses, including factors that increase the number of synaptic AMPA glutamate receptors (AMPARs). The levels of AMPARs at a synapse determine the size of the synaptic response, and the regulated addition and removal of AMPARs at synaptic sites is the molecular mechanism underlying learning and memory. AMPARs are tetramers and there are four subunits, GluA1-4, and functional receptors are composed of combinations of these e.g. GluA1 homomers or GluA2/3 heteromers. The functional properties of the AMPAR are determined by its subunit composition, for example the presence of the GluA2 subunit makes the channels impermeable to calcium, whilst GluA1 homomers are calcium permeable. We found that astrocytes secrete factors that increase the surface levels and synaptic accumulation of all AMPAR subunits in neurons by three-fold, thus strongly regulating neuronal activity. We identified the astrocyte-secreted proteins, glypican 4 and 6 (Gpc4 and 6), as sufficient to increase both the frequency and amplitude of glutamatergic synaptic transmission by recruiting the GluA1 subunit of the AMPAR to synaptic sites. These studies showed that Gpc4 specifically regulates GluA1 AMPARs, and that there are additional unknown astrocyte-derived signals that regulate the trafficking of other AMPA receptor subunits, i.e. GluA2/3 and GluA4. I will present data on our ongoing work to a) determine how Gpc4 recruits GluA1 to synapses, b) determine what regulates the expression and release of Gpc4 from astrocytes, c) determine the contribution of astrocyte-enriched glypican family members to synapse formation and function in vivo, d) identify the astrocyte-secreted factor that regulates GluA2 recruitment to synapses. Identifying the mechanisms that astrocytes use to regulate synaptic AMPARs has important implications for understanding how synaptic strength is normally regulated during development, how it is altered during learning and memory, and how it can be misregulated in neurological disorders such as autism and schizophrenia.

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September 12, 2016
Richard Daneman, Ph.D.

University of California, San Diego

Seminar will take place at 10:30 a.m. in the Indiana Memorial Union, Whittenberger Auditorium
during the 2016 Gill Symposium.

Title: The Blood-Brain Barrier in Health and Disease

Abstract: Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain.  This blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease.  Although the properties of the BBB are manifested in the endothelial cells, transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells.  Here we use a genomic, genetic and molecular approach to elucidate the cellular and molecular mechanisms that regulate the formation and function of the BBB.   We have identified a critical role for pericytes in regulating the permeability of CNS vessels by inhibiting the properties that make endothelial cells leaky. In particular pericytes limit the rate of transcytosis through endothelial cells as well as the expression of leukocyte adhesion molecules in CNS endothelial cells, which limits CNS immune infiltration. Furthermore, we have developed methods to highly purify and gene profile endothelial cells from different tissues, and by comparing the transcriptional profile of brain endothelial cells with those purified from the liver and lung, we have generated a comprehensive resource of transcripts that are specific to the BBB forming endothelial cells of the brain.    We have further examined the profile of CNS endothelial cells following injury and disease and have identified molecular mechanisms by which pericytes control BBB formation, which are then disrupted during neurological disease leading to BBB dysfunction. 

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September 12, 2016
Cagla Eroglu, Ph.D.

Duke University Medical Center

Seminar will take place at 2:10 p.m. in the Indiana Memorial Union, Whittenberger Auditorium
during the 2016 Gill Symposium.

Title: Control of Synaptic Connectivity by Astrocytes

Abstract: Astrocytes are highly complex cells with hundreds of thousands of fine processes that contact and ensheathe neuronal synapses. These perisynaptic astrocyte processes actively participate in synaptic development and function by regulating neurotransmitter release, maintaining ion homeostasis, and modulating synaptic connectivity. Despite the importance of astrocytes in synaptic development and function, we know very little about the molecular and cellular mechanisms that control the establishment of complex astrocyte morphology and astrocyte-synapse interactions.
            In our recent studies aiming to address this knowledge gap, we found that in the mouse visual cortex the establishment of the complex astrocyte morphology is a developmentally regulated process that occurs during a period of extensive synapse formation. Manipulation of visual experience during first three weeks of postnatal development, by dark rearing, strongly stunted cortical astrocyte development, indicating that experience-dependent changes in synaptic connectivity can alter morphological maturation of astrocytes.
How is the complex astrocyte morphology attained and remodeled? To mechanistically address this question, we developed in vitro and in vivo assays to conduct a candidate-based genetic screen to identify astrocytic cell adhesion molecules (CAMs) that control astrocyte development and synapse association. Surprisingly, we found that expression of neuroligin (NL) family CAMs, NL1, NL2 and NL3 control morphological maturation of astrocytes and their association with synapses both in vitro and in vivo. Our findings are in support of the following model: Astrocytic NLs control astrocyte morphological complexity by mediating astrocyte-synapse association via trans-cellular interactions with axonal/presynaptic neurexins and by regulating actin dynamics within astrocytes through their critical intracellular domains.
In summary our above findings provide a mechanistic insight into how complex astrocyte structure is attained during development and offer a new paradigm through which astrocytic NLs control brain development, a process that may be critically impaired in neurological disorders.

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September 13, 2016
Hugo Bellen, D.V.M., Ph.D.
Howard Hughes Medical Institute, Baylor College of Medicine

Seminar will be held in Mutlidisciplinary Science Building II (MSBII), Room 102 at 12:00 p.m.

Title: The fly eye as a discovery tool for human neurodegenerative disease

Abstract: We have used the fly eye to perform an electrophysiological screen that permitted the identification of 165 genes that cause neurodevelopmental and neurodegenerative phenotypes. More than 90% of these genes are conserved in human and 33% are already associated with human diseases.  These genes have already led to the discovery of several novel human diseases and have permitted the discovery of novel molecular mechanisms for 6 human neurodegenerative disease. 

Yamamoto et al., Cell, 2014.
Sandoval et al., PLos Biology, 2014.
Liu et al., Cell, 2015.
Jaiswal et al., PLoS Biology, 2015.
Bellen and Yamamoto, Cell, 2015.
Chen et al., eLife, 2016.
Li et al., eLife 2016

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October 10, 2016
Gregor Eichele, Ph.D.

Max Planck Institute for Biophysical Chemistry

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Active matter: intertwined cilia domains orchestrate complex fluid flow in the mammalian brain

Abstract: Cerebrospinal fluid (CSF) conveys many physiologically important signaling factors through the ventricular cavities of the brain. We investigated the transport of CSF in the third ventricle of the mouse and rat and discovered a highly organized pattern of cilia modules collectively giving rise to a network of fluid flows that allows for precise transport and cargo delivery within this ventricle. We also discovered a cilia-based switch that periodically alters the flow pattern so as to create a dynamic subdivision that may control cargo distribution in the third ventricle. Our work suggests that ciliated epithelia sustain hydrodynamic regulation of transport of CSF components

Co-sponsored with Program in Neuroscience

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October 28, 2016
Pascale Chavis, Ph.D.

French Institute of Health and Medical Research

Seminar will be held in Mutlidisciplinary Science Building II (MSBII), Room 102 at 12:00 p.m.

Title: Pending

Abstract: Pending

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October 31, 2016
Olivier Manzoni, Ph.D.

French Institute of Health and Medical Research

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Pending

Abstract: Pending

Co-sponsored with Program in Neuroscience

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January 30, 2017
Michal Schwartz, Ph.D.

Weizmann Institute of Science

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Pending

Abstract: Pending

Co-sponsored with Program in Neuroscience

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April 24, 2017
Andrew Holmes, Ph.D.

National Institutes of Health, National Institute on Alcohol and Abuse and Alcoholism

Seminar will be held in Psychology, Room 101 at 4:00 p.m.

Title: Pending

Abstract: Pending

Co-sponsored with Program in Neuroscience

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May 5, 2017
Chinfei Chen, M.D., Ph.D.

FM Kirby Neurobiology Center
Boston Children's Hospital
Harvard Medical School

Seminar will be held in Mutlidisciplinary Science Building II (MSBII), Room 102 at 12:00 p.m.

Title: Pending

Abstract: Pending

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