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Disrupted-in-Schizophrenia 1: a molecular key in microglia controlling mouse behaviour through cytoskeletal control
No full textMicroglia are the resident immune cells of the brain. In addition to their
immunological functions such as fighting infections, they are inseparable from
neuronal wiring through cytoskeleton-dependent mechanisms including synaptic
modulation and elimination. As such, disruption of microglial biology impacts
neurodevelopment, contributing to neurodevelopmental disorders such as
schizophrenia and autism spectrum disorder (ASD). Studying neurodevelopmental
risk genes as potential microglia-intrinsic regulators therefore adds to our growing
understanding of the fundamental biology underpinning microglial homeostatic
and immunological functions, and identifies novel mechanistic insights and
possible treatment options for neurodevelopmental disorders. We hypothesized
that disruption of the neurodevelopmental risk gene Disrupted-in-Schizophrenia 1
(DISC1) in microglia causes abnormal cytoskeletal control and subsequent
dysfunction of motion and phagocytosis, thereby driving neurodevelopmental
disorders.
We focused on DISC1 as a new molecular key that mediates microglial functions
in the developing mouse brain, from molecular control of cell biology up to
behavioural aspects after Disc1 impairment. Upon the validation of DISC1
expression in mouse and human microglia, we showed that Disc1 locus
impairment (LI) alters the inflammatory gene profile of primary mouse microglia
and halts nitric oxide production. Using raster image correlation spectroscopy, we
found that DISC1 diffuses slower in actin- and tubulin-rich regions of microglial
cells, suggesting cytoskeletal interaction and regulation. Also, actin distribution
and tubulin motion are altered in Disc1 LI microglia. On the level of cellular
morphology and motion, we combined in vitro and in situ techniques to show that
Disc1 LI hampers microglial morphological ramification, migration, branch motility
and phagocytosis of synaptosomes. We validated the microglial-autonomous role
of DISC1 on cell morphology and brain surveillance using a combination of wholebody irradiation, bone marrow transplantation and CSF1 receptor inhibition
(PLX5622) enabling the study of Disc1 LI microglia-like cells in a healthy, wildtype brain environment. Secondly, we revealed impairments in the daily behaviour and cognitive capacity
of adult full Disc1 LI mice, of which some can be fully rescued by transplanting
healthy, wild-type bone marrow inducing microglial replacement. The exact
contribution of the donated healthy microglia-like cells to the rescued behavioural
phenotype versus the contribution of the transplanted peripheral immune cells,
and the exact underlying mechanism remains to be further investigated.
Interestingly, the assessment of microglia-specific Disc1 LI on synaptic density
and function is already initiated in our lab.
We conclude that microglial immunological and homeostatic functions are
regulated by DISC1 through cytoskeletal control, which makes us among the first
to show a substantial role for a neurodevelopmental risk gene in microglial
physiology. In addition, our data indicate that the aberrant behaviours
characteristic of the Disc1 LI mouse model may be a result of immune system
dysregulation, including microglial dysfunction, and suggest that immunotherapy
or targeting of microglial-specific cytoskeletal pathways may represent future
therapeutic strategies for neurodevelopmental disordersMicroglia zijn de residente immuuncellen van de hersenen. Ze hebben
immunologische functies zoals het bestrijden van infecties, maar zijn ook
betrokken bij de ontwikkeling van de hersenen en het ontstaan en onderhouden
van neuronale netwerken. Dit doen ze bijvoorbeeld via synaptische modulatie en
eliminatie, twee mechanismen die sterk onderhevig zijn aan het dynamische
cytoskelet van microglia. Verstoring van microgliale functies beïnvloedt de
neurologische ontwikkeling en leidt mogelijks tot neuro-ontwikkelingsstoornissen
zoals schizofrenie en autismespectrumstoornis. Het bestuderen van neurologische
risicogenen als potentiële microglia-intrinsieke regulatoren draagt daardoor bij
aan onze kennis omtrent onderliggende mechanismen van microgliale
homeostatische en immunologische functies. Het identificeren van deze nieuwe
mechanismen leidt mogelijks tot nieuwe behandelingsopties voor neuroontwikkelingsstoornissen. Binnen dit doctoraatsproject veronderstelden we dat
verstoring van het neurologische risicogen Disrupted-in-Schizophrenia 1 (DISC1)
kan leiden tot abnormale controle van het cytoskelet in microglia. Dit bemoeilijkt
bijgevolg hun beweging en fagocytose, wat mogelijks neuroontwikkelingsstoornissen in de hand werkt.
We hebben ons ten eerste gefocust op DISC1 als een nieuw moleculair
mechanisme dat microgliale functies in ontwikkelende muizenhersenen
beïnvloedt. We hebben hiervoor zowel de moleculaire controle op celbiologie als
de gedragsveranderingen geïnduceerd door de afwezigheid van DISC1
bestudeerd. Na de validatie van DISC1 expressie in microglia van muizen en
mensen, toonden we aan dat Disc1 locus impairment (LI) het inflammatoire
genprofiel van primaire muis microglia verandert en de productie van
stikstofmonoxide verhindert. Met behulp van raster image correlation
spectroscopy ontdekten we dat DISC1 langzamer diffundeert in actine- en
tubulinerijke gebieden van microgliale cellen, wat wijst op cytoskeletale interactie
en regulatie. Ook zijn actinedistributie en tubulinebeweging veranderd in Disc1 LI
microglia. Op het niveau van celbiologie hebben we in vitro en in situ technieken
gecombineerd om aan te tonen dat Disc1 LI de microgliale morfologie, migratie,
motiliteit en fagocytose van synaptosomen belemmert. We hebben de microgliaspecifieke rol van DISC1 op celmorfologie en motiliteit gevalideerd door Disc1 LImicroglia-achtige cellen te bestuderen in een gezonde hersenomgeving met behulp van bestraling, beenmergtransplantatie en CSF1-receptorremming
(PLX5622).
Ten tweede onthulden we verstoringen in het dagelijkse gedrag en de cognitieve
capaciteit van volwassen Disc1 LI muizen. Sommige verstoringen konden echter
volledig hersteld konden worden door het transplanteren van gezond beenmerg
en hierdoor ook de Disc1 LI microglia te vervangen door gezonde microgliaachtige cellen. De exacte bijdrage van de gedoneerde gezonde microglia-achtige
cellen aan het herstelde gedragsfenotype ten opzichte van de bijdrage van de
getransplanteerde perifere immuuncellen, en het exacte onderliggende
mechanisme moet nog verder onderzocht worden. Hiervoor zijn we in het labo
intussen gestart om het effect van microglia-specifieke Disc1 LI te onderzoeken
op het aantal synapsen en op synaptische transmissie.
We concluderen dat microgliale immunologische en homeostatische functies
worden gereguleerd door DISC1 via cytoskeletale controle, wat ons een van de
eersten maakt die een substantiële rol voor een neuro-ontwikkelingsgen in
microgliale fysiologie heeft aangetoond. Bovendien geven onze resultaten aan dat
het afwijkende gedrag dat kenmerkend is voor het Disc1 LI muismodel het gevolg
kan zijn van een ontregeling van het immuunsysteem, inclusief disfunctie van
microglia. Dit suggereert dat immunotherapie of het beïnvloeden van
cytoskeletale mechanismen in microglia toekomstige therapeutische strategieën
voor neuro-ontwikkelingsstoornissen kunnen zijn
Mitochondrial trafficking in primary microglia cells is influenced by the TRPV4 ion channel
No full textMicroglia are highly dynamic cells that use a lot of energy to move around. Mitochondria are functional organelles that ensure energy for the fast cytoskeletal rearrangement that the microglia require. Microglia react to a disturbance in brain homeostasis by directed process extension and/ or migration towards a specific cue. Both types of microglial movement involve the reorganization of the cytoskeleton, which is dependent on the levels of Ca 2+ inside the cells. Recently, the temperature-sensitive ion channels, transient receptor potential vanilloid 4 (TRPV4) have been proven to aid in phagocytic motility either as a primary mechanism or as a mediator for other molecular cues. The activation of this channel increases the intracellular concentration of Ca 2+ and has been identified alongside proteins that are part of the cytoskeleton, such as actin. Adaptor proteins such as Miro and TRAK bind kinesin-1 and dynein to mitochondria and ensure the microtubule and actin-based movement of these organelles. Previously, mitochondrial trafficking was studied mostly in neurons and cancer cells, but not in the highly motile microglial cells. However, in regards to microglia and mitochondria, only metabolic studies have been performed so far. By performing tracking of the mitochondria in branched primary microglia we determined the baseline of the parameters, such as speed, distance, number of static mitochondria, anterograde and retrograde distances. These parameters are usually used in assessing the trafficking of this organelle in neurons. Due to these recordings, now mitochondrial movement can be compared between the two cell types. Recently, it has been demonstrated that by administering GSK2193874, a TRPV4 channel antagonist, the movement of microglial branches stops. We assessed what happens with the mitochondrial movements when the branches are immobile. This information can be compared to the homeostatic state in order to better understand the molecular mechanisms behind the mitochondrial movement. Understanding mitochondrial trafficking in microglia will help to elucidate the molecular mechanisms behind cell homeostasis and cell movement with the hopes of translating it into disease models
Mitochondrial trafficking in primary microglia cells is influenced by the TRPV4 ion channel
No full textMicroglia are highly dynamic cells that use a lot of energy to move around. Mitochondria are functional organelles that ensure energy for the fast cytoskeletal rearrangement that the microglia require. Microglia react to a disturbance in brain homeostasis by directed process extension and/ or migration towards a specific cue. Both types of microglial movement involve the reorganization of the cytoskeleton, which is dependent on the levels of Ca 2+ inside the cells. Recently, the temperature-sensitive ion channels, transient receptor potential vanilloid 4 (TRPV4) have been proven to aid in phagocytic motility either as a primary mechanism or as a mediator for other molecular cues. The activation of this channel increases the intracellular concentration of Ca 2+ and has been identified alongside proteins that are part of the cytoskeleton, such as actin. Adaptor proteins such as Miro and TRAK bind kinesin-1 and dynein to mitochondria and ensure the microtubule and actin-based movement of these organelles. Previously, mitochondrial trafficking was studied mostly in neurons and cancer cells, but not in the highly motile microglial cells. However, in regards to microglia and mitochondria, only metabolic studies have been performed so far. By performing tracking of the mitochondria in branched primary microglia we determined the baseline of the parameters, such as speed, distance, number of static mitochondria, anterograde and retrograde distances. These parameters are usually used in assessing the trafficking of this organelle in neurons. Due to these recordings, now mitochondrial movement can be compared between the two cell types. Recently, it has been demonstrated that by administering GSK2193874, a TRPV4 channel antagonist, the movement of microglial branches stops. We assessed what happens with the mitochondrial movements when the branches are immobile. This information can be compared to the homeostatic state in order to better understand the molecular mechanisms behind the mitochondrial movement. Understanding mitochondrial trafficking in microglia will help to elucidate the molecular mechanisms behind cell homeostasis and cell movement with the hopes of translating it into disease models
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Loss of TRPV4 is insufficient to promote repair in a spinal cord injury contusion model
No full textMicroglia, the primary phagocytes activated after spinal cord injury (SCI), play a key role in containing the lesion and protecting the glial scar from infiltrating immune cells. Although these responses are initially protective, excessive microglial proliferation and sustained pro-inflammatory activation can worsen secondary damage and limit recovery. Modulating microglial activity has been proposed as a potential therapeutic approach to enhance SCI repair. Previous studies suggest that constitutive loss of the mechanosensory channel TRPV4 (transient receptor potential vanilloid 4) reduces microgliosis and inflammation at the lesion site, improving functional outcomes. TRPV4 is a Ca2+-permeable channel implicated in several microglial characteristics, like morphology, motility, proliferation, and phagocytosis. Whereas endogenous TRPV4-activating stimuli are abundant at the lesion site, the microglia-specific contribution of TRPV4 in SCI recovery remains unknown. To investigate this, we used phagocyte-specific Trpv4 conditional knockout mice and phagocyte-specific TRPV4-deficient bone marrow chimeras subjected to contusion SCI. We achieved robust and efficient spinal cord monocyte-derived cell repopulation after bone marrow transplantation and PLX treatment. Surprisingly, TRPV4 deficiency in phagocytes did not enhance functional recovery, reduce microgliosis, or diminish scar formation after SCI. Furthermore, contrary to prior studies, constitutive TRPV4 deficiency did not improve SCI outcomes, indicating that the role of TRPV4 in this context is complex and potentially redundant with other pathways
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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