Dissertations / Theses on the topic 'Astrocyte'
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1
Cahoy, John David. "Genomic analysis of highly purified astrocytes reveals in vivo astrocyte gene expression : a new resource for understanding astrocyte development and function /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Adcock, K. H. "Astrocytic inhibition of neurite outgrowth at the Schwann cell/astrocyte interface." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.595362.
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The objectives of this thesis are to create a simplified in vitro model that mimics the neurite behaviour at the interface between the CNS and PNS and to overcome the repulsion by astrocytes. This has been achieved by co-culturing astrocytes and Schwann cells and monitoring neurite behaviour on them. In such a model neurites extending from a dorsal root ganglion explant exhibit a preference for Schwann cells and rarely cross the interface to grow onto astrocytes demonstrating that there is similarly between the model and the in vivo situation. Various molecules have been implicated in the guidance of neurite trajectories and several classes of these have been investigated in the course of this thesis. Two classes of molecules have been identified as having a role in guiding neurites at the Schwann cell/astrocyte interface: the first a cell adhesion molecule, L1, the second requires intracellular signalling events to be triggered by a neurotrophin and cyclic AMP. The production and regulation of a class of protease inhibitors, the TIMP family, by astrocytes in vivo and in vitro was also investigated. Astrocytes make at least 3 of these proteins which could also contribute to the general lack of neurite outgrowth seen on astrocytes when there is a choice between Schwann cells and astrocytes.
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Ghezali, Grégory. "Control of synaptic transmission by astroglial connexin 30 : molecular basis, activity-dependence and physiological implication." Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066423/document.
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Les astrocytes périsynaptiques participent activement, au côté des neurones, dans le traitement de l’information cérébrale. Une propriété essentielle des astrocytes est d’exprimer un niveau élevé de protéines appelées connexines (Cxs), et formant les sous-unités des jonctions communicantes. Étonnamment, bien qu’il ait été suggéré très tôt que la Cx30 astrocytaire soit impliquée dans des processus cognitifs, son rôle exact dans la neurophysiologie demeure cependant encore mal connu. Nous avons récemment révélé que la Cx30, via une fonction non-canal inédite, contrôle la force et la plasticité de la transmission synaptique glutamatergique de l’hippocampe en régulant les niveaux synaptiques de glutamate par le biais du transport astrocytaire du glutamate. Cependant, les mécanismes moléculaire et cellulaire impliqués dans ce contrôle, ainsi que sa régulation dynamique par l’activité neuronale et son impact in vivo dans un contexte physiologique restaient inconnus. Dans le cadre de cette problématique, j’ai démontré durant ma thèse que: 1) La Cx30 induit la maturation morphologique des astrocytes de l’hippocampe par l’intermédiaire de la modulation d’une voie de signalisation dépendante de la laminine et régulant la polarisation cellulaire ; 2) l’expression de la Cx30, sa localisation perisynaptique, ainsi que ses fonctions sont modulées par l’activité neuronale ; 3) Le contrôle de la couverture astrocytaire des synapses du noyau supraoptique de l’hypothalamus par la Cx30 fixe les niveaux plasmatiques de base de la neurohormone ocytocine et ainsi favorise la mise en place de comportements sociaux adaptés. Dans l’ensemble, ces résultats éclairent les régulations des Cxs astrocytaires par l’activité neuronale et leur rôle dans le développement postnatal des réseaux neurogliaux, ainsi que dans le contrôle des interactions structurelles astrocytes-synapses à l’origine de processus comportementauxPerisynaptic astrocytes are active partners of neurons in cerebral information processing. A key property of astrocytes is to express high levels of the gap junction forming proteins, the connexins (Cxs). Strikingly, astroglial Cx30 was suggested early on to be involved in cognitive processes; however, its specific role in neurophysiology has yet been unexplored. We recently reveal that Cx30, through an unconventional non-channel function, controls hippocampal glutamatergic synaptic strength and plasticity by directly setting synaptic glutamate levels through astroglial glutamate clearance. Yet the cellular and molecular mechanisms involved in such control, its dynamic regulation by activity and its impact in vivo in a physiological context were unknown. To answer these questions, I demonstrated during my PhD that: 1) Cx30 drives the morphological maturation of hippocampal astrocytes via the modulation of a laminin signaling pathway regulating cell polarization; 2) Cx30 expression, perisynaptic localization and functions are modulated by neuronal activity; 3) Cx30-mediated control of astrocyte synapse coverage in the supraoptic nucleus of the hypothalamus sets basal plasmatic level of the neurohormone oxytocin and hence promotes appropriate oxytocin-based social abilities. Taken together, these data shed new light on astroglial Cxs activity-dependent regulations and roles in the postnatal development of neuroglial networks, as well as in astrocyte-synapse structural interactions mediating behavioral processes
4
Stringer, Charles Edward Alexander. "Calcium dependent astrocyte-neuron communication." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/32690.
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The discovery of direct communication between astrocytes and neurons has
changed the perception of astrocytes from passive support cells to active partners in
information processing. Astrocytes express myriad neurotransmitter receptors and have
been shown to release neurotransmitters, allowing these cells to respond and signal to
adjacent neurons, respectively. Astrocytes can rapidly respond to neurotransmitters with a
rise in [Ca²⁺]i and astrocyte neurotransmitter release has been shown to be calcium
dependent. The purpose of this research was to investigate unknown aspects of astrocyteneuron
communication with in situ calcium imaging to improve our understanding of
how these cells interact functionally.
The first objective of this research was to determine whether extracellular
dopamine elicits astrocyte calcium transients in the prefrontal cortex (PFC). Astrocytes
from this area express dopamine receptors and dopamine is an important neurotransmitter
in the PFC. We found that astrocytes in PFC brain slices reliably respond to a high
concentration of dopamine ([50μM]) with [Ca²⁺]i transients, however these responses
were due to the activation of adrenoreceptors, not dopamine receptors. The inability of a
lower concentration of dopamine ([10μM]) to elicit astrocyte [Ca²⁺]i transients questions
the whether these cells can rapidly respond to PFC dopamine at physiological levels.
The second objective of this research was to investigate the extent that calcium
dependent glutamate release from astrocytes is able to influence neural activity. The best
studied mechanism of astrocyte gliotransmitter release is the calcium dependent release
of glutamate which has been demonstrated in single astrocytes in situ. We used the vasoactive peptide endothelin to preferentially elicit widespread astrocyte [Ca²⁺]i
transients astrocytes from hippocampal brain slices to determine whether the widespread
calcium rise in astrocytes was associated with a change in glutamate sensitive synaptic
transmission. Despite eliciting nearly ubiquitous astrocyte calcium responses, we
observed no change in glutamate sensitive synaptic transmission as measured by
extracellular field recordings. These results question the ability of astrocytes to acutely
influence synaptic transmission of a brain region.
Our findings do not support an acute role of calcium dependent communication
between astrocytes and neurons in rapid information processing in the systems we
investigated.Medicine, Faculty of
Graduate
5
Smith, Maria Civita. "MAPPING ASTROCYTE DEVELOPMENT IN THE DORSAL CORTEX OF THE MOUSE BRAIN." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1373039738.
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Stewart, Courtney Elizabeth. "Astrocyte Development and Function is FGF8 Signaling Dependent." Kent State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=kent1556290142104336.
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Thorén, Anna. "Astrocyte metabolism following focal cerebral ischemia /." Göteborg : Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Göteborg University, 2006. http://hdl.handle.net/2077/744.
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Boycott, Hannah Elizabeth. "Hypoxic modulation of astrocyte glutamate transporters." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445941.
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Johnstone, S. R. "Rodent astrocyte sub-types in vitro." Thesis, Imperial College London, 1985. http://hdl.handle.net/10044/1/37737.
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PELASSA, SIMONE. "Signalling from astrocyte processes in CNS." Doctoral thesis, Università degli studi di Genova, 2021. http://hdl.handle.net/11567/1043545.
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The role of astrocytes in the Central Nervous System (CNS) has been increasingly recognized in the last decades. Astrocytes, indeed, not only support neurons but also play a key role in signal transmission in CNS releasing gliotransmitters as glutamate and participating to the tripartite synpases.
Here, astrocytes function in signal transmission was modeled using ex-vivo models purified from adult rat brain, named gliosomes.
Using the perfusion technique, release from gliosomes was tested in three different contexts:
- glutamate release associated to receptor-receptor interactions,
- exosomes release,
- glutamate release evoked by photobiomodulation stimulation.
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Richard, Chloé. "Implication des connexines gliales dans les atteintes de la Neuromyélite Optique : un rôle dans la démyélinisation et les altérations neuronales." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1075/document.
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La Neuromyélite Optique (NMO) est une maladie auto-immune démyélinisante, rare et grave, du système nerveux central (SNC). Elle est caractérisée par une démyélinisation et une perte axonale ciblant principalement le nerf optique et la moelle épinière. La découverte d'un auto-anticorps (IgG-NMO) dirigé contre l'aquaporine-4 (AQP4), un canal hydrique exprimé par l'astrocyte, a été une étape clé dans la compréhension de la physiopathologie de la NMO, actuellement définie comme une astrocytopathie. La pathogénicité de l'IgG-NMO a été démontrée : il induit une internalisation d'AQP4 et des transporteurs au glutamate, provoquant une altération de la fonction astrocytaire. Cependant les mécanismes permettant de lier la dysfonction astrocytaire aux altérations caractéristiques de la NMO, notamment la démyélinisation, restent méconnus. Les astrocytes sont des cellules gliales essentielles à l'établissement et au maintien de l'homéostasie du SNC. Ils permettent la régulation des flux hydriques et ioniques, le contrôle extracellulaire des neuromédiateurs ainsi que l'apport de métabolites énergétiques aux neurones et aux oligodendrocytes. Ils sont aussi caractérisés par une très forte expression de connexines (Cx), des molécules transmembranaires s'assemblant sous une forme hexamérique : le connexon. Les connexines forment soit des hémicanaux, permettant l'échange de petites molécules entre les milieux intra- et extra-cellulaires, soit des jonctions communicantes par la juxtaposition de connexons appartenant à deux cellules, assurant le couplage intercellulaire avec le passage de petites molécules et d'ions (ATP, glutamate, lactate, calcium). Les fonctions hemicanal et jonction communicante sont fortement régulées en condition physiologique et altérées en condition pathologique, notamment en contexte neuroinflammatoire. Nous émettons l'hypothèse que les IgG-NMO altèrent l'expression et la fonction des connexines, et conduisent ainsi à la production d'un environnement toxique pour les oligodendrocytes et la myéline, et délétère pour le fonctionnement neuronal. Mon projet de thèse avait trois objectifs : i) la caractérisation du phénotype astrocytaire induit par les IgGNMO ; ii) l'identification d'altérations des connexines et leur implication dans la pathologie ; iii) la mise en évidence d'altérations de la transmission synaptique induites par les IgG-NMO et l'implication de connexines dans cet effet. Des modèles de cultures primaires gliales traitées par des IgG-NMO issue d'une cohorte de patients m'ont permis de caractériser le phénotype acquis par les astrocytes, et de proposer le concept d'un astrocyte réactif spécifique de pathologie. Les astrocytes réactifs spécifiques de la NMO induisent un milieu inflammatoire spécifique et toxique, provoquant une démyélinisation. Grâce au développement d'une coculture gliale et neuronale produisant des neurones myélinisés, et à l'utilisation de peptides inhibiteurs des Cx, j'ai pu montrer que les NMO-IgG ont un effet démyélinisant et que celui-ci implique les Cx. La démyélinisation est en effet associée à des modifications structurales et fonctionnelles des Cx astrocytaires, observées à la fois in vitro et dans notre modèle in vivo, le rat-NMO. Enfin, la mise en place d'une étude électrophysiologique en potentiel de champs local sur des tranches d'hippocampe de rats m'a permis d'étudier l'effet des IgG-NMO sur la transmission glutamatergique basale. J'ai pu mettre en évidence un effet dépresseur des IgG-NMO, partiellement bloqué par un inhibiteur de connexines, la carbenoxolone. Comme il a déjà été démontré par des études cliniques dans des pathologies neurodégénératives, l'utilisation de modulateurs de Cx semble être une voie thérapeutique prometteuse afin de prévenir la démyélinisation et les altérations du fonctionnement neuronal de la NMONeuromyelitis Optica (NMO) is a rare and severe auto-immune demyelinating disease of the central nervous system (CNS). It is characterized by demyelination and axonal loss targeted to the optic nerve dans the spinal cord. The identification of a specific autoantibody (NMO-IgG) directed against the astrocytic protein AQP4 was a key step in the understanding of NMO physiopathology: it is now considered as an astrocytopathy. NMO-IgG is also a biomarker of NMO, and its pathogenicity has been demonstrated. NMO-IgG induce an internalization of AQP4 together with other membrane proteins such à glutamate transport GLT1. This could alter astrocyte functions but the mechanisms connecting astrocytopathy and demyelination remain unclear. Astrocytes are abundant glial cells crucial for the establishment and the maintenance of CNS homeostasis. They regulate water flux and ion homeostasis and control extracellular volume and neurotransmitter concentrations. They also provide neurons and oligodendrocytes with energy substrates. Astrocytes are characterized by a high expression of connexins (Cx), transmembrane proteins assembling in hexameric form, called connexon. Cx form either hemichannels, unopposed connexon at the membrane, allowing the exchange of small molecules (<1,2kDa e.g. glutamate, ATP) and ions (Ca2+, K+) between extra- and intra-cellular compartments. Cx also form gap junctions, formed by the juxtaposition of two connexons at the membrane of two different cells, and allow the quick cell to cell exchange of small molecules, metabolites and ions (e.g. glucose, lactate, Ca2+). Hemichannel and gap junction functions are tightly regulated under physiological conditions and can be altered in pathological condition for example during neuroinflammation. We proposed that NMO-IgG by altering connexins expression and/or function could lead to the production of a toxic environment for oligodendrocytes and myelin but also for neuronal functioning. This feature of astrocyte dysfunction could participate to NMO alterations. My thesis project had three main goals: i) the characterisation of astrocyte phenotype induced buy NMO-IgG, ii) the identification of connexins alterations and their implication NMO physiopathology, iii) the highlight of synaptic alterations induced by NMO-IgG and the involvement of connexins in this effect. Primary glial cell cultures treated with NMO-IgG from a cohort of NMO patients, were used to characterize astrocyte phenotype and we proposed the concept of a specific reactive dysfunctioning astrocyte induced by NMO-IgG. Those astrocytes, called “NMO-astrocytes” are responsible for the production of a proinflammatory toxic microenvironment for oligodendrocytes and leading to demyelination. With the development of a myelinated culture model, composed of glial cells and neurons with myelinated axons, together with the use of specific inhibitors of Cx functions, we showed that NMO-IgG induced demyelination involved connexin dysfunction. In fact, demyelination was associated with structural and functional alterations of astrocytic connexins observed both in vitro and in vivo in the NMO-rat model. Electrophysiological recording of basal glutamatergic synaptic activity in the rat hippocampus showed a strong depression of synaptic responses induced by NMO-IgG. Connexins could be implicated in this alteration since blocking all connexins with carbenoxolone blocked NMO-IgG effect
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Griffin, Susan. "Astrocyte-neuron communication following an ischaemic insult." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446691/.
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Ischaemia results from the cessation of blood flow to all or part of the brain, causing a rapid depletion of O2 and impairment of oxidative phosphorylation. Bioenergetic failure follows within minutes, which precipitates directly immediate neuronal death. Upon reperfusion, despite the return of energy substrates, further neuronal death can occur up to several days later, depending on the severity of the initial insult. Astrocytes have been shown to be considerably more resistant to ischaemia/reperfusion injury than neurones and may play either a neuroprotective role or indeed exacerbate the neuronal injury. We have explored the possible interactions between astrocytes and neurones following ischaemia using an in vitro model of ischaemia/reperfusion injury, as a controlled environment that lends itself more easily to manipulation of the numerous variables involved in such an insult. As such we have produced an oxygen glucose deprivation model. We have constructed a chamber in which O2 can be lowered to a concentration of 1 M. We have further developed a primary cortical neuronal culture that is 99% pure and which can survive to at least 10 days in vitro. We have additionally established a novel system for the co-culture of astrocytes and neurones in order to study the communication between these cells in a manner that can allow the complete separation of one cell-type from another. Astrocytes cultured alone do not exhibit signs of cell death during reperfusion of 24hrs duration following ischaemia of up to 2hrs whereas neuron cultures show profound cell death following an ischaemic period of only 15mins. We have co-cultured neurones, which have been subjected to a 15min ischemic insult, with either non-insulted astrocytes or astrocyte conditioned medium during the reperfusion stage. Results show that both astrocytes and astrocyte-conditioned medium enhance neuronal survival. We have finally investigated possible mechanisms to account for this.
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Hochstim, Christian John Bronner-Fraser Marianne Anderson David J. "A homeodomain code specifies astrocyte positional identity /." Diss., Pasadena, Calif. : Caltech, 2007. http://resolver.caltech.edu/CaltechETD:etd-07262008-115538.
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Paumier, Adrien. "Evaluation du canal calcique TRPA1 comme cible thérapeutique potentielle dans la pathogénèse de la maladie d’Alzheimer TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide." Thesis, Université Grenoble Alpes, 2020. http://www.theses.fr/2020GRALV010.
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La maladie d'Alzheimer (MA) est une maladie neurodégénérative qui affecte progressivement les fonctions cognitives et la mémoire. Le cerveau des personnes atteintes de la MA est caractérisé par le dépôt extracellulaire d'amyloïde-β (Aβ), un peptide qui s'agrège au sein de structures appelées "plaques séniles". Cependant, il a été reconnu que les formes solubles oligomériques d’Aβ (Aβo) sont les formes du peptide qui déclenchent la pathologie. Elles sont impliquées dans des dysfonctionnements synaptiques qui sont considérés comme l'un des premiers événements de la MA. Des études récentes suggèrent que les astrocytes pourraient jouer un rôle majeur dans les dysfonctionnements synaptiques, mais leur implication dans les premiers stades de la MA reste peu documentée. En utilisant l'imagerie calcique, nous avons montré que l'application brève d’Aβo sur des tranches aiguës de cerveau de souris induit une hyperexcitabilité calcique astrocytaire dans l'hippocampe. Cette hyperexcitabilité est indépendante de l'activité neuronale et se produit dans les microdomaines des prolongements astrocytaires impliqués dans la formation des synapses tripartites. Dans la même échelle de temps, nous avons observé une hyperactivité au sein des neurones voisins, en utilisant des enregistrements par patch-clamp en configuration cellule entière. Cette hyperactivité dépend de la signalisation calcique dans le réseau astrocytaire. De manière intéressante, l'inhibition du canal calcique TRPA1, exprimé dans les astrocytes, bloque l'effet d’Aβo et restaure l'activité des astrocytes et des neurones à un niveau basal. Par ailleurs, l'inhibition chronique de TRPA1 dans le modèle de souris APP/PS1-21 de la MA bloque les perturbations neuronales et astrocytaires précliniques et prévient les troubles de l'apprentissage. En somme, ce travail de thèse suggère un rôle essentiel pour l'hyperexcitabilité précoce astrocytaire dans la pathogenèse de la MA, et souligne que TRPA1 est une cible thérapeutique prometteuse avec un effet neuroprotecteurAlzheimer’s disease (AD) is a neurodegenerative disorder that progressively affects cognitive functions and memory. AD brains are characterized with the extracellular deposition of amyloid-β (Aβ), a peptide that aggregates in structures named “senile plaques”. However, it has been recognized that oligomeric soluble forms of Aβ (Aβo) are the pathology-triggering form of the peptide. They are involved in synaptic dysfunctions which are thought to be one of the earliest events in AD. Recent studies suggest that astrocyte could play a major role in synaptic dysfunctions but their involvement in early stages of AD remained largely undefined. By using calcium imaging we showed that short term application of Aβo on mice acute brain slices induces astrocytic calcium hyperexcitability in the hippocampus. This hyperexcitability was independent of neuronal activity and occurred in the astrocyte processes microdomains involved in tripartite synapses formation. In the same time-scale, we observed hyperactivity in neighboring neurons, using whole-cell patch-clamp recordings, which depends on calcium signaling in astrocyte network. Strikingly, the inhibition of astrocytic calcium channel TRPA1 blocked the effect of Aβo and reversed both astrocyte and neuron activity toward physiological range. Interestingly, chronic inhibition of TRPA1 in APP/PS1-21 mouse model of AD, blocked both neuron and astrocyte dysfunctions at preclinical stages and prevented learning impairments. Overall, this thesis work suggests a critical role for early astrocyte hyperexcitability in pathogenesis of AD and highlights TRPA1 as an interesting therapeutic target with neuroprotective effect
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CHARLTON, JULIE ANN. "NEURAL ACTIVITY AFFECTS ASTROCYTE MORPHOLOGY IN DROSOPHILA MELANOGASTER." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/612643.
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Astrocytes are known to maintain a proper ionic balance in the central nervous system, take up neurotransmitters after synaptic signaling, and modulate synaptic activity through a reciprocal conversation in which neuronal activity induces responses in glial cells that, in turn, modulate neuronal activity. We previously reported that constitutive RNAi knockdown of the GABA transporter in astrocyte--‐like glia of the 3rd--‐instar ventral nerve cord (VNC) strongly reduced larval locomotion, indicating that altering astrocyte function modulates activity in neurons comprising the motor circuitry (MacNamee et al., SfN abstract 2013). Here we have manipulated neural activity in the larva to assess the impact of altered neuronal activity on astrocytes. We fed larvae picrotoxin, which blocks GABAA receptors and glutamate--‐gated chloride channels and used a FLP--‐out genetic construct to visualize the detailed morphology of astrocytes in the VNC. Results to date indicate that the pharmacological treatment, which would be expected to change the balance of inhibition and excitation, significantly reduced locomotor activity and concomitantly led to a marked decrease in the volume occupied by the branching processes of astrocytes. The impact on glial morphology is being assessed using 3--‐D reconstructions of high--‐magnification confocal microscopic images.
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Hoke, Ahmet. "Astrocyte proteoglycans in a model of reactive gliosis." Case Western Reserve University School of Graduate Studies / OhioLINK, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=case1057944965.
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Dhar, Doel. "Exploring Electric Field-Induced Changes in Astrocyte Behavior." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3174.
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Electric fields, which are generated by the movement of charged ions across membranes, are found in all biological systems and can influence cellular components ranging from amino acids to biological macromolecules. Physiological field strengths range from 1 – 200 mV/mm, and these electric fields are especially elevated at sites of cellular growth during development and regeneration. It has previously been demonstrated that elevated electric fields induce alignment of astrocyte processes in vitro, enhancing the rate of neurite outgrowth. It is believed that electric fields of varying physiological strength affect other astrocytic responses associated with regeneration. To characterize the duration over which these changes emerge, cultured rat astrocytes were exposed to different direct-current electric field strengths. The resulting cellular behaviors were recorded every three minutes with an inverted microscope equipped with DIC optics and a stage incubator. Electric fields were found to induce astrocyte responses similar to those observed during periods of neurodevelopment and regeneration. Changes in astrocyte movement, proliferation, & morphology emerged within the first hour and persisted through the course of the electric field application, leading mammalian astrocytes to revert to an earlier maturation state resembling those seen in amphibian astrocytes associated with central nervous system regeneration. Collectively, these results suggest that applied electric fields lead to astrocyte dedifferentiation, with certain electric field strengths eliciting and enhancing specific cell responses.
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Singh, Sandeep. "Novel mechanism in astrocyte gene regulation and function." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/112.
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This dissertation sheds light on several novel mechanistic findings in astrocyte specific gene regulation and function by the NFI-X transcription factor which can be further extrapolated to astrocyte differentiation and glial tumor invasion. First, we cloned and analyzed human NFI-X3, a novel splice variant of the nfix gene, which contains a unique transcriptional activation (TA) domain completely conserved in primates. In contrast to previously cloned NFI-X1, overexpression of NFI-X3 potently activates NFI reporters, including GFAP reporter, in astrocytes and glioma cells. The expression of NFI-X3 is dramatically upregulated during the differentiation of neural progenitors to astrocytes and precedes the expression of astrocyte markers such as GFAP and SPARCL1. Overexpression of NFI-X3 dramatically upregulates GFAP and SPARCL1 expression in glioma cells, while the knockdown of NFI-X3 diminishes the expression of both GFAP and SPARCL1 in astrocytes. Although activation of astrocyte-specific genes involves DNA demethylation and subsequent increase of histone acetylation, the TA domain of NFI-X3 activates GFAP expression by inducing alteration in the +1 nucleosome architecture that lead to the increased recruitment of RNA polymerase II. Thus, we propose that NFI-X3 is the major isoform of NFI-X regulating astrocyte specific gene expression during their differentiation, likely via nucleosomal remodeling of the astrocyte specific promoters. NFI-X knock-out animals display severe neuroanatomical defects including partial agenesis of the corpus callosum and hydrocephalus, however the target genes of NFI-X in the CNS remained elusive. Here, we show for the first time that YKL-40 is a novel target gene of NFI-X in astrocytes and controls their migration. In addition, we report that YKL-40 expression is activated during mouse brain development and also during the differentiation of neural progenitors into astrocytes in vitro. In primary astrocytes, YKL-40 expression is controlled by nuclear factor I-X (NFI-X) and signal transducer and activator of transcription 3 (STAT3), which are known to regulate gliogenesis. Indeed, knock-down of NFI-X and STAT3 significantly reduced YKL-40 expression in astrocytes, while overexpression of NFI-X3 (a splice isoform of NFI-X) dramatically induced YKL-40 expression in glioma cells. In addition, activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes. Interestingly, STAT3 activated YKL-40 expression via its binding site located in the YKL-40 proximal promoter, whereas direct NFI-X binding had not been detected. Surprisingly, NFI-X and STAT3 physically interact and this complex likely regulates YKL-40 expression in astrocytes. We further show that NFI-X controls migration and invasion of astrocytes and glioma cells, respectively, by regulating YKL-40 expression. These novel data suggest that YKL-40 is expressed by astrocytes during brain development and controls astrocyte migration. Since YKL-40 is used as a shared biomarker for ongoing inflammation and oncogenic transformation and its (high) levels correlate to the severity of disease, we have tested its expression in astrocytes and microglia (CNS macrophage) after treatment of various neuro-inflammatory cytokines. Here we report, that IL-1 and IL-6/OSM synergistically activate YKL-40 expression in astrocytes but not in microglia when added together. Furthermore, induced YKL-40 expression can be detected in the media from astrocytes but not from microglia. Since YKL-40 is a secreted molecule and is highly upregulated in CSF of multiple sclerosis patients, we have tested its role in oligodendrocyte differentiation. Preliminary observations clearly demonstrate that YKL-40 inhibits myelin basic protein (MBP) expression during the in-vitro differentiation of oligodendrocyte progenitor cells into myelin producing oligodendrocytes. Thus, we propose that YKL-40 is produced and secreted by reactive astrocytes during various CNS pathologies, and may inhibit MBP expression in MS. In summary, these studies have identified novel mechanisms in astrocyte gene regulation and functions, and provided new insights into astrocyte biology, with the implications for further understanding of the development and progression of CNS pathology.
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Bakmiwewa, Supun Madushani. "The Astrocyte: a Crossroads in Cerebral Malaria Pathogenesis." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14952.
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Cerebral malaria (CM) is a severe complication of malaria, and involves the central nervous system (CNS). Despite the significant negative impact of CM, its pathogenesis is not fully understood. Two theories, namely cerebral hypoxia and cytokine expression, are considered to be involved in the process. The present study investigated the potential interaction of these two theories in driving the development of CM. Astrocytes can be a major determinant of the outcome of CNS diseases, and we hypothesised that astrocytes, by responding to the pathways involved in the two theories, would drive the development of CM. The cytokines interferon-gamma (IFN-γ) and lymphotoxin-alpha (LT-α) are essential for the development of experimental CM in a murine model. The chemokine C-X-C motif ligand 10 (CXCL10) also is implicated in this process. Both Malawian paediatric and mouse CM brain samples showed increased cytokine expression and astrocyte activation. Furthermore, by the use of Ifnγ-/- mice, it was shown that IFN-γ was involved in this CM-associated astrocyte activation. Cultured human primary astrocytes were directly activated by IFN-γ and LT-α to produce synergistic levels of CXCL10. This finding provides a potential mechanism by which astrocytes could be involved in the pathogenesis of CM, and sheds light on the possible role of LT-α in CM. Hypoxia had an effect on astrocytes, but their response to cytokines was not altered by hypoxia. However, oxygen-glucose deprivation resulted in a decline in cytokine-induced CXCL10 release by cultured astrocytes. Decreased production of CXCL10 has the potential to translate into less blood brain barrier damage. Thus, the mechanisms underlying these two theories do interact at the astrocyte level, but astrocytes show both protective and pathological features as a result of this interaction. The present thesis shows that it is unlikely that the two mechanisms act together to reinforce the astrocytes’ pathological effects to cause CM.
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Blaszczyk, Lucie. "Etude des cellules astrocytaires et microgliales thalamiques dans un modèle de douleur neuropathique chez le rat." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0081/document.
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La douleur chronique est une pathologie invalidante de longue durée notamment caractériséepar trois symptômes : l’allodynie (un stimulus non douloureux est perçu comme douloureux),l’hyperalgésie (un stimulus douloureux est perçu comme encore plus douloureux) et desdouleurs ambulatoires. Quand cette douleur est due à une lésion ou une dysfonction du systèmenerveux on parle de douleur neuropathique. Chez les patients et les modèles animaux dedouleurs neuropathiques, les études ont montré que les neurones thalamiques étaienthyperexcitables. Les cellules gliales, astrocytes et microglies, sont des partenaires synaptiquesimpliqués dans la transmission et la plasticité synaptique et pourraient être impliqués dans cephénomène. En effet, ces cellules peuvent modifier leur phénotype lorsque le système nerveuxest affecté, elles sont réactives : leur morphologie est hypertrophiée, l’expression d’ARNm et deprotéines comme iba-1 (ionized binding-adaptor molecule 1) et CD11b/c (cluster ofdifferentiation 11b/c) pour les cellules microgliales et GFAP (glial fibrillary acidic protein) etS100β (S100 calcium binding protein β) pour les cellules astrocytaires est augmentée. Ellespeuvent également libérer des molécules pro-inflammatoires. Tout ceci pourrait générer ouamplifier l’hyperexcitabilité des neurones présents dans le thalamus.Mon travail de thèse a consisté en l’étude des astrocytes et de la microglie thalamique dans lemodèle de douleurs neuropathiques de ligature des nerfs spinaux L5-L6 du nerf sciatique (spinalnerve ligation, SNL). Les symptômes d’allodynie et d’hyperalgésie mécaniques ont étécaractérisés par le test des filaments de von Frey et les douleurs ambulatoires par le test dedistribution pondéral dynamique. L’expression des ARNm de marqueurs gliaux a été étudiée parune approche de qRT-PCR sur des prélèvements thalamiques et sur des noyaux thalamiquesobtenus par microdissection au laser. L’expression neurochimique des marqueurs iba-1,CD11b/c, Cathepsine S, GFAP et S100β a été étudié par immunohistofluorescence en quantifiantle nombre de cellules immunopositives et la surface occupée par les marqueurs. Toutes cesexpériences ont été réalisées à J14 et J28 après la chirurgie.A J14, les animaux SNL développent des symptômes d’allodynie et d’hyperalgésie mécaniqueainsi que des douleurs ambulatoires. Chez ces animaux, les cellules microgliales thalamiquesprésentent des signes de réactivité avec l’augmentation de l’expression des ARNm desmarqueurs CTSS et CX3CR1, le récepteur de la fractalkine, marqueurs connus pour leursimplications dans l’hyperexcitabilité neuronale spinale en conditions de douleursneuropathiques. De plus, l’expression neurochimique des marqueurs gliaux étudiés est diminuéece qui se traduit notamment par une diminution du nombre de cellules immunopositives pources marqueurs chez les animaux SNL. A J28, les symptômes douloureux sont maintenus. De plus,la réactivité microgliale décelée à J14 par qRT-PCR est toujours présente avec l’augmentation del’expression de l’ARNm codant pour la fractalkine (CX3CL1), partenaire de la voieCTSS/CX3CR1/CX3CL1. La diminution de l’expression neurochimique thalamique desmarqueurs gliaux chez les animaux SNL était transitoire et n’est plus présente à J28. Enrevanche, des signes de réactivité astrocytaire thalamique ont été mis en évidence chez lesanimaux SNL.Ainsi, ce travail dévoile une ambivalence au niveau des altérations de la glie thalamique dans cemodèle SNL: une diminution précoce de l’expression des marqueurs gliaux thalamiques suivied’une réactivité astrocytaire plus tardive concomitante à des signes de réactivité microgliale. Denombreuses expériences sont encore nécessaires pour appréhender l’impact de cetteambivalence gliale thalamique inédite dans un contexte de douleur neuropathiqueChronic pain is an incapacitating and long lasting pathology mainly characterized by threesymptoms: allodynia (a non painful stimulus is perceived as painful), hyperalgesia (a painfulstimulus is perceived as more painful) and ambulatory pains. When chronic pain is due to alesion or dysfunction of nervous system it is called neuropathic pain. In both patients and animalmodels of neuropathic pain, researchers found that thalamic neurons are hyperexcitable. Glialcells, astrocytes and microglia, are strong synaptic partners involved in synaptic transmissionand plasticity and therefore could be involved in this phenomenon. Indeed, these cells canmodify their phenotype when nervous system is damaged. They become reactive: theirmorphology is hypertrophied, mRNA and protein expression of iba-1 (ionized binding-adaptormolecule 1) and CD11b/c (cluster of differentiation 11b/c) for microglia and GFAP (glialfibrillary acidic protein) and S100β (S100 calcium binding protein β) for astrocytes is increased.They could also release pro-inflammatory molecules. All of these could contribute to generate oramplify the thalamic neuronal hyperexcitability.In my PhD work I studied thalamic astrocytes and microglia in a rat neuropathic pain model ofL5-L6 spinal nerves ligation (SNL). Mechanical allodynia and hyperalgesia were characterizedwith von Frey filament test and ambulatory pain with dynamic weight bearing apparatus. mRNAexpression of glial markers were studied with qRT-PCR technique on thalamic punches andlaser-microdissected nuclei. Neurochemical expressions of iba-1, CD11b/c, cathepsin S, GFAPand S100β markers were quantified using an immunohistofluorescence approach to count thenumber of immunopositive cells and surface stained by these markers. All these experimentswere done at D14 and D28 after surgery.At D14, SNL animals develop mechanical allodynia and hyperalgesia as well as ambulatory pain..For these animals, thalamic microglial cells showed signs of reactivity with the increase mRNAexpression of CTSS and CX3CR1, fractalkine receptor, well known markers involved in spinalneuronal hyperexcitability under neuropathic pain conditions. In addition, the number ofimmunopositive cells for the glial markers is decreased in SNL animals. At D28, the neuropathicpain symptoms are still present. Furthermore, thalamic microglial reactivity found at D14 withqRT-PCRm method is still present with the increased mRNA expression of fractalkine (CX3CL1),partner of CTSS/CX3CR1/CX3CL1 pathway. The decreased neurochemical expression of glialmarkers found at D14 was transient as I didn’t find this result at D28. However, thalamicastrocytic reactivity was found at D28 in SNL animals.So, this work reveal a new glial process at thalamic level in this SNL model of neuropathic pain :an early decreased expression of glial markers and then a later thalamic astrocytic reactivityconcomitant with signs of thalamic microglial reactivity. Numerous studies are required toexplore the role of such novel ambivalent glial alterations in the context of neuropathic pain
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Sitar, Sandra M. "Effects of oxidative stress and propofol on astrocyte function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ39884.pdf.
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Vangoor, Vamshidhar [Verfasser]. "Overexpression of CPEB3 leads to astrocyte dysfunction / Vamshidhar Vangoor." Bonn : Universitäts- und Landesbibliothek Bonn, 2013. http://d-nb.info/1044971533/34.
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Forsyth, Robert J. "The contribution of astrocyte glycogen to brain energy homeostasis." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361387.
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Jakobson, Katherine. "The role of phosphatidic acid in astrocyte intracellular signalling." Thesis, Open University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293615.
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Yung, Hong Wa. "Regulation of astrocyte cell death by kinase signalling pathways." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620576.
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Bushong, Eric Allen. "Astrocyte domains in the rat hippocampus and their development /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3112856.
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King, C. M. "The role of resting Ca2+ in astrocyte Ca2+ signalling." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1474498/.
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Astrocytes form gap-junction coupled networks and their fine processes cover many synapses enabling astrocytes to powerfully modulate synapse function. Such modulation is thought to involve Ca2+ -dependent release of signalling molecules from astrocytes. However, astrocyte Ca2+ signalling and its role in synaptic physiology remains a matter of debate. An incomplete and mostly qualitative understanding of the fundamental mechanisms of intracellular Ca2+ signalling in astrocytes could be a knowledge-limiting factor. Previous studies predict that astrocyte resting [Ca2+] profoundly affects astrocyte Ca2+ signalling, especially IP3 and store-dependent Ca2+ transients. I therefore quantitatively investigated the role of resting [Ca2+] in shaping spontaneous and evoked Ca2+ transients in astrocytes. I used two-photon excitation fluorescence microscopy and whole-cell patch clamp to document Ca2+ signalling of individual passive astrocytes in the CA1 stratum radiatum of acute hippocampal slices in young adult rat. I used fluorescence lifetime imaging to obtain a quantitative readout of astrocyte [Ca2+] and reveal the relationship between resting [Ca2+] and Ca2+ transients. I combined these techniques with UV-uncaging of Ca2+ or Ca2+ buffer to manipulate the astrocyte resting [Ca2+] to further investigate its effect on Ca2+ signalling. Using these methods, we have found that low resting [Ca2+] were associated with smaller amplitudes of spontaneous Ca2+ transients. This was also true for metabotropic glutamate receptor agonist (DHPG) evoked Ca2+ transients when different cells or regions of interest of the same cell were compared. The well-established increase of most IP3 receptors’ open probability at higher cytosolic [Ca2+] could explain this observation. In contrast, changes of resting [Ca2+] within a single astrocyte region were associated with inverse changes in amplitude of evoked Ca2+ transients. The DHPG-induced equilibration of [Ca2+] across cytosol and store compartments could be a potential explanation for this effect. Thus, resting [Ca2+] could shape the amplitude of astrocyte Ca2+ transients by at least two distinct mechanisms.
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Eraso, Pichot Abel. "Adaptive regulation of calcium excitability and energy metabolism by CREB-dependent transcription in astrocytes: study of the mechanisms governing astrocyte plasticity." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/664170.
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Cada cop més evidencies suggereixen que els astròcits participen en les altes funcions cerebrals, controlant des de la transmissió sinàptica fins a les ones cerebrals globals i els processos d’aprenentatge i memòria. Diferents mecanismes han sigut proposats com a responsables d’aquests processos mediats per astròcits, entre ells, l’alliberació de gliotransmissors a partir de les senyals de calci així com la de lactat semblen els principals efectors. L’existència d’aquest control de les funcions cerebrals per part dels astròcits suggereix que aquestes cèl·lules poden regular les funcions cerebrals en resposta a experiència tan com les neurones, constituint el fenomen de plasticitat astrocitària. En neurones s’ha demostrat que el conegut factor de transcripció CREB, coordina les plasticitats sinàptica i intrínseca. El fet que, en astròcits, l’activació de CREB també està regulada per activitat cerebral, situa aquest factor de transcripció com a la diana ideal per promoure canvis dependents d’activitat en astròcits. En aquesta tesi hem analitzat l’efecte de l’activació de la transcripció depenent de CREB en astròcits, centrant-nos en l’excitabilitat del calci i en el metabolisme d’aquestes cèl·lules. Hem demostrat que l’activació de la transcripció depenent de CREB redueix les senyals citosòliques de calci a través del mitocondri a la vegada que augmenta l’alliberació de lactat, dos canvis que poden tenir impacte en la transmissió sinàptica. Una altra contribució important d’aquest estudi es l’anàlisi molecular dels mitocondris dels astròcits, que ha revelat que aquestes cèl·lules poden utilitzar metabòlits que no són glucosa, com ara àcids grassos, per respondre a les necessitats metabòliques energètiques. Els nostres resultats estableixen el CREB en astròcits con un eix de la plasticitat astrocitària i revelen la interacció entre la plasticitat i el metabolisme energètic en astròcits. Aquests descobriments constitueixen un avenç mecanístic i conceptual en el coneixement de la biologia dels astròcits i com aquestes cèl·lules poden controlar l’aprenentatge i la memòria.An increasing body of evidence suggests that astrocytes participate in higher-brain functions, controlling from synaptic transmission to global brain waves and learning and memory processes. Different mechanisms have been proposed to mediate these astrocyte-dependent processes, astrocytic lactate release and calcium-dependent gliotransmission being the main known effectors. The existence of control of brain functions by astrocytes suggests that astrocytes may shape brain functions in response to experience as much as neurons, thus constituting the phenomenon of astrocyte plasticity. In neurons, the transcription factor CREB is the best known coordinator of synaptic and intrinsic plasticity. The fact that, in astrocytes, CREB activation is also activity-dependent, positions CREB as an ideal target to promote plasticity-related changes in astrocytes, too. In this thesis, we have analyzed the effect of the activation of CREB-dependent transcription in astrocytes, specifically regarding calcium signals and metabolism. We have demonstrated that activation of CREB-dependent transcription reduces cytosolic calcium events via mitochondria and increases in lactate release, which may have impact on synaptic transmission. An important contribution of the study is the molecular analysis of astrocytic mitochondria, which has revealed that astrocytes may use fuels other than glucose such as fatty acids to meet basic energy metabolic demands. Taken together, our results establish astrocytic CREB as a hub in astrocyte-plasticity and shed light on the interplay between plasticity and energy metabolism in astrocytes; these findings constitute a conceptual and mechanistic advance in the knowledge of astrocytic biology and how these cells may control learning and memory.
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Abjean, Laurene. "Les astrocytes réactifs, des partenaires anti-agrégants dans la maladie de Huntington : identification des mécanismes impliqués dans le dialogue neurone-astrocyte." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS088.
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La maladie de Huntington (MH) est une maladie neurodégénérative causée par une extension de répétitions du codon CAG dans le gène de la Huntingtine (Htt). Cette maladie est caractérisée par la mort des neurones striataux et la présence d’agrégats de Htt mutée (mHtt). De plus, au cours de la MH, les astrocytes, qui sont essentiels au bon fonctionnement neuronal, changent d’état et deviennent réactifs. La réactivité astrocytaire est caractérisée par des changements morphologiques et transcriptomiques mais l’impact fonctionnel de cette réactivité reste peu compris.Afin d’étudier le rôle des astrocytes réactifs dans la MH, nous avons utilisé des vecteurs viraux récemment développés par notre équipe, qui induisent ou bloquent la réactivité astrocytaire in vivo en ciblant la voie JAK2-STAT3. Nous avons montré que les astrocytes réactifs diminuent le nombre et la taille des agrégats de mHtt majoritairement présents dans les neurones. Ceci est associé à l’amélioration de plusieurs altérations neuronales observées dans ces modèles. Une analyse transcriptomique réalisée sur des astrocytes réactifs révèle des changements majeurs d’expression de gènes liés aux systèmes de protéostasie. De plus, l’activité du lysosome et du protéasome est augmentée dans les astrocytes réactifs de souris modèles de la MH. Nous montrons également que les astrocytes réactifs éliminent plus efficacement leurs propres agrégats de mHtt, suggérant qu’au cours de la MH, ces cellules pourraient dégrader plus efficacement la mHtt provenant des neurones. De plus, certaines protéines chaperonnes sont induites dans les astrocytes réactifs. En particulier, la co-chaperonne DNAJB1/Hsp40 est surexprimée dans les astrocytes réactifs et est retrouvée dans les exosomes isolés à partir de striata de souris MH. Des expériences de gain et perte de fonction suggèrent que cette chaperonne est impliquée dans les effets bénéfiques des astrocytes réactifs sur l’agrégation de la mHtt et l’état des neurones. Les astrocytes réactifs pourraient donc libérer des protéines anti-agrégantes qui favorise l’élimination de la mHtt dans les neurones.Notre étude montre que les astrocytes peuvent, en devenant réactifs au cours de la MH, acquérir des propriétés bénéfiques pour les neurones et favoriser, via un dialogue complexe avec les neurones, l’élimination des agrégats de mHttHuntington’s disease (HD) is a hereditary neurodegenerative disease caused by an expansion of CAG codons in the Huntingtin gene. It is characterized by the death of striatal neurons and the presence of mutant Huntingtin (mHtt) aggregates. In pathological conditions, as in HD, astrocytes change and become reactive. Astrocyte reactivity is characterized by morphological and significant transcriptomic changes. Astrocytes are essential for the proper functioning of neurons but the functional changes associated with reactivity are still unclear.To better understand the roles played by reactive astrocytes in HD, we took advantage of our recently developed viral vectors that infect selectively astrocytes in vivo and either block or induce reactivity, through manipulation of the JAK2-STAT3 pathway. We used these vectors in two complementary mouse models of HD and found that reactive astrocytes decrease the number and the size of mHtt aggregates that mainly form in neurons. Reduced mHtt aggregation was associated with improvement of neuronal alterations observed in our mouse models of HD. A genome-wide transcriptomic analysis was performed on acutely sorted reactive astrocytes and revealed an enrichment in genes linked to proteolysis. Lysosomal and proteosomal activities were also increased in reactive astrocytes in HD mice. Moreover, we show that reactive astrocytes degrade more efficiently their own mHtt aggregates, suggesting that these cells could siphon mHtt away from neurons. Alternatively, several chaperones were induced in reactive astrocytes. In particular, the co-chaperone DNAJB1/Hsp40 was upregulated in reactive astrocytes and was present in exosomal fraction from HD mouse striatum. Loss and gain of function experiments suggest that this chaperone is involved in the beneficial effects of reactive astrocytes on mHtt aggregation and neuronal status. Therefore, reactive astrocytes could release anti-aggregation proteins that could promote mHtt clearance in neurons.Overall, our data show that astrocytes, by becoming reactive in HD, develop a protective response that involves complex bidirectional signaling with neurons to reduce mHtt aggregation
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Ducourneau, Vincent. "Réactivité gliale et transmission glutamatergique/glycinergique spinale dans un modèle de douleur cancéreuse osseuse chez le rat : approches comportementale, immunohistochimique, moléculaire et biochimique." Thesis, Bordeaux 2, 2013. http://www.theses.fr/2013BOR22008/document.
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Au vu de la relative inefficacité des traitements actuels de la douleur cancéreuse osseuse (DCO) il est devenu nécessaire aujourd'hui d'identifier de nouvelles cibles (cellulaires et/ou moléculaires) pour développer de nouveaux outils thérapeutiques. Dans ce contexte, ces dernières années, de nombreuses études ont suggéré que les cellules gliales, principalement les astrocytes et la microglie, pourraient contribuer au développement et au maintien de la douleur chronique. D'autre part, dans des modèles d'études précliniques de la DCO, plusieurs auteurs ont récemment constaté une réactivité astrocytaire importante dans les cornes dorsales de la moelle épinière et ont montré que, si on empêche cette réactivité, les symptômes douloureux sont diminués. Cependant, la relation exacte existant entre la réactivité des cellules gliales et les symptômes douloureux en condition de DCO est inconnue. Afin de décrypter cette relation, nous avons dans un premier temps étudié le décours temporel des comportements douloureux et caractérisé l’état de sensibilisation centrale dans un modèle de DCO chez le rat induit par l'injection de cellules de carcinome glandulaire mammaire (MRMT-1) dans le tibia. Nous montrons par des approches radiologiques, comportementales (tests de douleur évoquée et de distribution pondérale dynamique) et immunohistochimiques (immunodétection de la protéine Fos après palpation non douloureuse de la patte) que les animaux cancéreux MRMT développent graduellement une tumeur osseuse (premiers signes au 10ème jour post-inoculation), une allodynie et une hyperalgésie mécaniques (à partir du 10ème jour) et thermiques (à partir du 14ème jour), un inconfort de la patte injectée (à partir du 14ème jour ) et des phénomènes de sensibilisation centrale. Dans un deuxième temps, nous avons recherché des indices structuraux et fonctionnels de réactivité gliale spinale dans notre modèle de DCO. L'objectif était donc de dater l'apparition de la réactivité gliale, et de déterminer la nature des cellules gliales impliquées : microglie et/ou astrocytes. Nous montrons par des approches immunohistochimiques qu’aucun signe morphologique de réactivité astrocytaire ni microgliale n’est observable pendant l’établissement et le maintien de la DCO alors que ces signes existent dans un modèle de douleur neuropathique (ligature de nerfs spinaux). De plus, par des approches moléculaire (qRT-PCR) et biochimique (technique du Bio-Plex) nous montrons que, parmi les 20 marqueurs structuraux et fonctionnels de réactivité gliale testés, seule l’expression de l’aquaporine 4 (un canal à eau spécifique des astrocytes) est significativement augmentée en condition de DCO. Nos résultats suggèrent donc que les astrocytes et les cellules microgliales jouent des rôles différents dans la douleur cancéreuse et dans la douleur neuropathique. Enfin, dans un troisième temps, nous avons cherché à mettre en évidence une implication des astrocytes dans la pathologie DCO au travers d’une caractérisation des transmissions glutamatergique et glycinergique, qui sont toutes deux fortement modulées par l’environnement astrocytaire. Par la quantification de l’expression de l’ARNm (qRT-PCR) et par dosage des taux d’acides aminés (électrophorèse capillaire), nous montrons que les principaux acteurs (transporteurs, récepteurs, agonistes et co-agonistes) de la transmission glutamatergique et glycinergique spinale ne subissent pas d’altération significative en condition de DCO. En conclusion, nous montrons que des symptômes douloureux chroniques peuvent se développer et se maintenir (1) sans signe d’astrogliose et de réactivité microgliale spinale ; et (2) sans altération de l’expression des principaux acteurs de la transmission spinale glutamatergique et glycinergique. Nos résultats invitent donc à revoir le lien très fort qui est fait actuellement entre douleur chronique et astroglioseThe relative lack of efficiency of current treatments used to relieve bone cancer pain prompts to the identification of new molecular and/or cellular targets for the development of new therapeutic strategies. In that context, a large number of recent studies have suggested the involvement of glial cells, among which astrocytes and microglial cells, in the onset and maintenance of chronic pain symptoms. In few animal models of bone cancer pain, several authors have recently evidenced an increased glial reactivity in spinal cord dorsal horn, and demonstrated that preventing astrocytic reactivity was sufficient to reduce pain symptoms in these models. However, the exact relationship of glial reactivity with bone cancer pain symptoms remains poorly understood. In order to decipher this link, we have first studied the temporal development of pain symptoms, and characterized the degree of central sensitization in a rat model of bone cancer pain induced by the injection of mammary gland carcinoma cells (MRMT-1) in the tibial bone. Using radiologic assessment of tumor development, behavioral measurements to quantify evoked (von Frey hairs) and spontaneous (dynamic weight bearing) pain and immunodetection of Fos after non nociceptive palpation of cancer bearing limb, we demonstrate that animals injected with MRMT-1 cells gradually develop a bone tumor (first detectable 10 days after inoculation), a mechanical allodynia and hyperalgesia (first noticeable at day 10), and later on a thermal allodynia and hyperalgesia (first detectable at day 14) as well as discomfort of the injected limb (day 14) and finally central sensitization phenomenons. Second, we have investigated the presence of structural and functional markers of spinal glial reactivity in our model of bone cancer pain. Our objectives were to date the onset of spinal glial reactivity, for microglial and astrocytic cells. Using immunohistochemical approaches, we show that none of the classical markers of astrocytic and microglial reactivity can be observed during the onset and the persistent phase of bone cancer pain whereas the markerswere easily identified in a neuropathic pain model (spinal nerve ligation). Furthermore, using molecular (qRT-PCR) as well as biochemical (Bio-Plex) approaches, we show that among the 20 structural and functional markers of glial reactivity tested, only aquaporin-4 displays increased mRNA levels in bone cancer pain model. Hence, our results suggest that astrocytes and microglial cells play different roles in bone cancer and neuropathic pain. Finally, we tried to evidence the involvement of astrocytes in bone cancer pain by characterizing glutamatergic and glycinergic synaptic transmission, both of which are heavily modulated by astrocytic environment. By quantifying mRNA levels (qRT-PCR) and measuring the level of inhibitory and excitatory amino acids (capillary electrophoresis), we show that the main actors (transporters, receptors, agonists and co-agonists) of glutamatergic and glycinergic transmissions in the spinal cord do not undergo any significant alteration in bone cancer pain conditions. We conclude that chronic painful symptoms may develop and persist (1) without any sign of astrogliosis or enhanced microglial reactivity in the spinal cord, and (2) without any alteration in the expression/levels of the main actors involved in glutamatergic and glycinergic transmission. These results therefore question the strong link that is frequently made between astrogliosis and chronic pain
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Latour, Alizée. "Influence des Acides Gras Poly-Insaturés n-3 (oméga3) sur les intéractions Neurones/Astrocytes au cours du vieillissement cérébral : aspects cognitifs et cellulaires." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112081.
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Un statut pauvre en Acides Gras Poly-Insaturés ω3 (AGPI ω3), favorisé par une alimentation occidentale comportant un faible ratio en ω3/ω6, semble contribuer au déclin cognitif chez les personnes âgées, mais les mécanismes cellulaires impactés sont encore mal connus. Nous avons donc étudié l’influence du statut en ω3 sur l’évolution de la neurotransmission glutamatergique et des fonctions astrocytaires au cours du vieillissement dans l’hippocampe de rats. Ces processus sont impliqués dans la formation de la mémoire et leurs dérégulations participent aux dommages cérébraux conduisant au déclin cognitif. Nous avons comparé 6 groupes de rats agés de 6 et 22 mois nourris avec un régime déficient en ω3, équilibré en ω3/ω6 ou supplémenté en ω3 (huile de poisson) : Jeunes équilibrés (JEq), déficients (JDef) ou supplémentés (JSup) et Agés équilibrés (AEq), déficients (ADef) ou supplémentés (ASup). Nous avons évalué l’efficacité synaptique et la plasticité (enregistrements électrophysiologiques), les fonctions astrocytaires (capture de glutamate et expression de la GFAP), les marqueurs neuronaux (transporteurs et récepteurs du glutamate), les capacités cognitives (Openfield et Labyrinthe de Barnes) et analysé la composition lipidique cérébrale. Les manipulations nutritionnelles d’apport en ω3 modifient efficacement l’incorporation de l’acide docosahexaénoïque (DHA, principale ω3 des membranes cellulaires) dans le cerveau (-50% deficient vs équilibré, +10% supplementé vs équilibré). Le vieillissement induit une diminution de 35% de l’efficacité synaptique en raison d’une baisse de la libération de glutamate pré-synatique, et une diminution de 30% de la capture de glutamate associé à une astrogliose conséquente (+100% GFAP). La déficience en ω3 acentue les effets du vieillissement (rats ADef vs AEq: -35% efficacité synaptique, -15% capture de glutamate, +30% GFAP). Al’inverse, la supplémentation en ω3 améliore l’efficacité synaptique (rats ASup vs AEq +25%) et semble inhiber l’astrogliose chez le rat âgé (ASup vs JEq : pas de modification de la GFAP). Les tests comportementaux montrent que le vieillissement a des effets plus marqués chez les déficients en ω3 et au contraire atténués chez les supplémentés. Nos résultats révèlent des altérations de la synapse glutamatergique de l’hippocampe au cours du vieillissement aggravées par la déficience en ω3 et atténuées par la supplémentation en ω3. Afin d’évaluer l’influence du statut en ω3 sur l’activation astrocytaire, des modèles in vitro d’astrocytes « âgés » et « activés » par des cytokines inflammatoires dont l’augmentation à bas bruit est caractéristique du vieillissement cérébral, ont été développésA poor ω3 polyunsaturated fatty acids (ω3 PUFA) status, favored by the low ω3/ω6 ratio in western diets, seems to contribute to cognitive decline in the elderly, but mechanistic evidence is lacking. We therefore explored the impact of ω3 status on the evolution of glutamatergic transmission and astrocytic functions in the hippocampus during ageing in rats. These processes are involved in memory formation and their dysregulation participates to the age-related brain damage leading to cognitive decline. We have compared 6 groups of rats aged 6 to 22 months fed ω3-deficient, ω3/ω6-balanced, or ω3 (fish oil) supplemented diets: Young ω3 Balanced (YB), Deficient (YD) or Supplemented (YS), and Old ω3 Balanced (OB), Deficient (OD) or Supplemented (OS) rats. We have evaluated synaptic efficacy and plasticity (electrophysiological recording), astroglial regulations (glutamate uptake and GFAP expression), neuronal markers (glutamate transporters and receptors), cognitive abilities (Barnes maze and Openfield) and analyzed brain fatty acids composition. Dietary modulation of ω3 intakes efficiently modified the incorporation of docosahexaenoic acid (DHA, the main ω3 in cell membranes) in brain (-50% deficient vs balanced, +10% supplemented vs balanced). Ageing induced a 35% reduction of synaptic efficacy due to decreased pre-synaptic glutamate release, and a 30% decrease in the astroglial glutamate uptake associated to a marked astrogliosis (+100% GFAP). ω3 deficiency further decreased these hallmarks of ageing (OD vs OB rats: -35% synaptic efficacy, -15% glutamate uptake, +30% GFAP). On the opposite, ω3 supplementation increased synaptic efficacy (+25% OS vs OD) and seems to abolish astrogliosis (OS vs YS : no change in GFAP). Behavioural tests showed some increased effects of age in deficient rats and attenuated effects in supplemented ones. Our results characterize some specific age-related alterations of the glutamatergic synapse in the hippocampus that are aggravated by a dietary deficit in ω3 and attenuated by ω3 supplementation. In order to explore ω3 status on astrocytic activation, in vitro models of “old” astrocytes and “activated” by inflammatory cytokines which characterize the low-grade inflammation in brain aging, have been developed
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Smih, Fatima. "Contribution à l'étude des ligands endogènes des récepteurs des benzodiazépines. Localisation, caractérisation et effet in vitro des endozépines sur les astrocytes de rat en culture." Rouen, 1993. http://www.theses.fr/1993ROUES016.
Full textAbstract:
Les endozépines forment une famille de peptides dont le chef de file est le diazepam-binding inhibitor (DBI). Initialement isolées à partir du cerveau de rat, les endozépines sont considérées comme des ligands endogènes des récepteurs des benzodiazépines (BZ). En utilisant des anticorps dirigés contre l'octadécaneuropeptide (ODN, 33-50 DBI), nous avons montré par RIA que les endozépines sont largement distribuées dans les tissus périphériques du rat. L'étude de la localisation de ces peptides par immunohistochimie et hybridation in situ a révélé que les endozépines sont stockées et synthétisées par des cellules spécialisées dans le tube digestif (cellules caliciformes et entérocytes) et le testicule (cellules de Leydig). L'analyse par HPLC et électrophorèse sur gel de polyacrylamide d'extraits de tissus périphériques et de cerveau révèlent l'existence de deux formes de masse moléculaire distincte: l'une de 4000 Da correspondant au triakontatétraneuropeptide (TTN, 17-50 DBI) et celle de 6000 Da à une forme allongée du TTN. L'utilisation des techniques d'immunohistochimie et d'analyse par HPLC ont révélé que les astrocytes en culture primaire conservent leur capacité à synthétiser le peptide de 6000 Da. La mesure de la concentration du calcium intracellulaire ([Ca2+]i) dans des astrocytes par microfluorimétrie a montré qu'à faibles doses (10 puissance -10 à 10 puissance -8 M) l'ODN provoque une augmentation de [Ca2+]i, alors que des concentrations plus élevées d'ODN (10 puissance -6 et 10puissance -5 M) diminuent la [Ca2+]i. Les antagonistes des récepteurs des BZ de type central (flumazenil) ou périphérique (PK 11195) ne modifient pas l'augmentation du calcium induite par l'ODN. En revanche, le flumazenil bloque l'effet inhibiteur de l'ODN; ce dernier s'effectue donc via l'activation de récepteurs centraux des BZ. A forte concentration le potassium provoque une augmentation rapide suivie d'une diminution du [Ca2+]i. La phase d'inhibition est bloquée par le flumazenil. Parallèlement le potassium augmente la libération du peptide 6000 Da, indiquant que les endozépines sont produites par les astrocytes et peuvent agir de façon paracrine ou autocrine. Ces données suggèrent que les endozépines sont des facteurs pleiotropes de la communication cellulaire, qui pourraient jouer un rôle important dans le fonctionnement des glandes endocrines et du système nerveux central
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Edwards, Malia Michelle 1975. "Alteration of astrocyte-specific protein expression : implications for Alzheimer's disease." Monash University, Dept. of Psychology, 2002. http://arrow.monash.edu.au/hdl/1959.1/7859.
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Shearer, Morven Caroline. "The astrocyte/meningeal cell interface : a barrier to nerve regeneration." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620558.
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Heckers, Sandra [Verfasser]. "Astrocyte functions during cuprizone-induced de- and remyelination / Sandra Heckers." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2018. http://d-nb.info/1162356774/34.
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West, Heloise Joan. "Control of retinal astrocyte numbers during development of the retina." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405230.
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Parviainen, Lotta. "Astrocyte-neuron interactions in the juvenile form of Batten Disease." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/astrocyte-neuron-interactions-in-the-juvenile-form-of-batten-disease(566b0c58-a020-44ef-834c-8e7a64e6dcc5).html.
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The neuronal ceroid lipofuscinosis (NCLs, Batten Disease) are inherited, fatal neurodegenerative disorders of childhood. In all forms of NCL, astrocyte activation occurs early in the disease and precedes neuronal loss. However, in the most common juvenile form (JNCL), which is caused by a mutation in the Cln3 gene, this astrocyte response appears to be compromised. Since astrocytes are crucial for the functioning and survival of neurons, and emerging evidence highlights the pivotal role that reactive astrocytosis plays in the pathogenesis of CNS diseases, any deficits in the biology of these cells could significantly impact neuronal health. In order to study the functioning of JNCL astrocytes, these cells were isolated from a well-characterised mouse model of the disease, Cln3 deficient mice (Cin3-l- mice), and their basic biology characterised. These studies revealed that Cln3-l- astrocytes have a disrupted actin and intermediate filament cytoskeleton. Possibly due to these defects, Cln3-l- astrocytes have an attenuated ability to response to an activation stimulus, just as observed in vivo, and to divide and migrate. They also display pronounced defects in their ability to take-up glutamate and to secrete a range of proteins, including cytokines, neuroprotective factors and the anti-oxidant glutathione, that become even more evident upon stimulation. Additionally, their impaired calcium signalling suggests that communication might be altered in these cells. Most importantly, using a co-culture system, these Cln3-l- glia were shown to negatively impact the health of both Cln3-l- and wild-type neurons, with the mutant neurons being the most severely affected, probably because of their own compromised biology. This includes a reduction in neurite complexity and displacement of the axon initial segment (AIS), which modulates neuronal excitability and the initiation of axon potentials. Thus, these data show, for the first time, that JNCL astrocytes are functionally compromised and might play an active role in the neurodegeneration observed in JNCL. Further, this information raises the possibility that, in future, astrocytes should be considered as targets for therapeutic interventions.
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Slezak, Michal. "New transgenic mouse models for astrocyte-specific, inducible somatic mutagenesis." Université Louis Pasteur (Strasbourg) (1971-2008), 2007. https://publication-theses.unistra.fr/public/theses_doctorat/2007/SLEZAK_Michal_2007.pdf.
Full textAbstract:
Les astrocytes, qui représentent la population cellulaire majoritaire dans le système nerveux central, jouent un rôle dans la synaptogénèse, la transmission synaptique, les processus homéostatiques et développementaux. Malheureusement, la plupart des données concernant les astrocytes proviennent d’études in vitro. Mon projet a donc consisté à générer de nouvelles lignées de souris transgéniques permettant d’induire spécifiquement dans les astrocytes des manipulations géniques. Ces lignées transgéniques expriment la Cre ERT2 recombinase sous le contrôle de promoteurs astrocytaires (ApoE, Aqp4, Cx30 et Glast). Alors que les lignées Tg(ApoE-CreERT2) et Tg(Aqp4-CreERT2) presentent un faible taux de recombinaison médiée par la Cre recombinase dans le cervau, les lignées Tg(Cx30-Cre ERT2) et Tg(Glast-CreERT2) ont-elles un fort taux de recombinaison. Comme la recombinaison a lieu spécifiquement dans les astrocytes, ces deux lignées pourront servir d’outil de pointe afin de mieux cerner le rôle des astrocytes in vivoAstrocytes, being the most numerous cell population in the central nervous system play a role in synaptogenesis, synaptic transmission, homeostatic processes and development. Unfortunately, most of the data concerning astrocytes comes from in vitro studies. Therefore in my project I have generated new transgenic mouse lines enabling inducible gene manipulation specifically in astrocytes. In these lines tamoxifen-inducible Cre-ERT2 recombinase is expressed under the control of astrocyte-specific promoters: ApoE, Aqp4, Cx30 and Glast). Whereas in lines Tg(ApoE-Cre ERT2) and Tg(Aqp4-Cre ERT2) the level of Cre-mediated recombination is low in the brain, the strong Cre activity was detected in Tg(Cx30-Cre-ERT2) and Tg(GLAST-Cre ERT2) lines. Since the recombination was shown to be astrocyte-specific, the latter two lines shall serve for better understanding the role of astrocytes in vivo
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Pirttimäki, T. M. "Astrocyte-neuron signalling by synaptic stimulation in the ventrobasal thalamus." Thesis, Aston University, 2009. http://publications.aston.ac.uk/15371/.
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In the Ventrobasal (VB) thalamus, astrocytes are known to elicit NMDA-receptor mediated slow inward currents (SICs) spontaneously in neurons. Fluorescence imaging of astrocytes and patch clamp recordings from the thalamocortical (TC) neurons in the VB of 6-23 day old Wistar rats were performed. TC neurons exhibit spontaneous SICs at low frequencies (~0.0015Hz) that were inhibited by NMDA-receptor antagonists D-AP5 (50µM), and were insensitive to TTX (1µM) suggesting a non-neuronal origin. The effect of corticothalamic (CT) and sensory (Sen) afferent stimulation on astrocyte signalling was assessed by varying stimulus parameters. Moderate synaptic stimulation elicited astrocytic Ca2+ increases, but did not affect the incidence of spontaneous SICs. Prolonged synaptic stimulation induced a 265% increase in SIC frequency. This increase lasted over one hour after the cessation of synaptic stimulation, so revealing a Long Term Enhancement (LTE) of astrocyte-neuron signalling. LTE induction required group I mGluR activation. LTE SICs targeted NMDA-receptors located at extrasynaptic sites. LTE showed a developmental profile: from weeks 1-3, the SIC frequency was increased by an average 50%, 240% and 750% respectively. Prolonged exposure to glutamate (200µM) increased spontaneous SIC frequency by 1800%. This “chemical” form of LTE was prevented by the broad-spectrum excitatory amino acid transporter (EAAT) inhibitor TBOA (300µM) suggesting that glutamate uptake was a critical factor. My results therefore show complex glutamatergic signalling interactions between astrocytes and neurons. Furthermore, two previously unrecognised mechanisms of enhancing SIC frequency are described. The synaptically induced LTE represents a form of non-synaptic plasticity and a glial “memory” of previous synaptic activity whilst enhancement after prolonged glutamate exposure may represent a pathological glial signalling mechanism.
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Slezak, Michal Pfrieger Frank. "New transgenic mouse models for astrocyte-specific, inducible somatic mutagenesis." Strasbourg : Université Louis Pasteur, 2007. http://eprints-scd-ulp.u-strasbg.fr:8080/824/01/SLEZAK_Michal_2007.pdf.
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Cammarota, Mario. "Reciprocal neuron-astrocyte signaling in epileptic seizure generation and propagation." Doctoral thesis, Università degli studi di Padova, 2013. http://hdl.handle.net/11577/3426301.
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The idea that astrocytes – the main population of glial cells in the brain – are active
partners of neurons in many aspects of brain functions represented a Copernican
Revolution in neurobiology. Astrocytes, which were for many years considered just
like the cement (from Greek glia i.e. glue) that keeps neuronal cells together, have
now been moved from the periphery to the centre of the universe of information
processing in the brain providing a radically different point of observation in the study
of brain physiology. This new view of brain activity turns around the discovery of a
bidirectional communication between neurons and astrocytes, a process called
gliotransmission. Astrocytes respond to neurotransmitters and through a Ca2+
dependent mechanism release neuroactive substances that induce functional
changes in neurons. In spite of the resistances opposed against the desertion of the
neuronal dogma, a large amount of evidence collected during the last three decades
contributed to reshape the concept of synaptic communication, considering astrocytes
- together with the pre- and post- synaptic membranes - a fundamental element of
the tripartite synapse. In other words, astrocytes participate transversally to
information processing in the brain by modulating both synaptic transmission and
different forms of plasticity.
This new consciousness of astrocytes as active elements in brain physiology,
naturally suggests that these glial cell can potentially be involved in the development
of brain disorders. Indeed many studies revealed that dysfunctions in astrocyteneuron
signaling can be directly involved in many pathologies including Alzheimer’s
disease, Parkinson disease, amyotropic lateral sclerosis and epilepsy.
The main goal in my thesis was to understand how the release of gliotrasnmitters by
astrocytes, in particular glutamate, may influence two distinct phases of epileptic
activity: the generation and the propagation of a focal seizure.L'idea che gli astrociti - la popalazione di cellule gliali più importante del cervello - sono partner attivi dei neuroni in molte delle funzioni del sistema nervoso, ha rappresentato una Rivoluzione Copernicana nello studio della neurobiologia. Per molti anni considerati alla stregua di un cemento (dal greco glia, colla) con l'unica funzione di tenere insieme i neuroni, gli astrociti sono riconosciuti oggi rivestire un ruolo centrale nel processamento dell'informazione. Questa nuova visione del funzionamento cerebrale si fonda sulla scoperta di una comunicazione bidirezionale tra neuroni ed astrociti, processo chiamato gliotrasmmissione. Gli astrociti rispondono ai neurotrasmettitori, ed attraverso un meccanismo calcio dipendente, possono a loro volta rilasciare sostante neuroattive che possono indurre cambiamente funzionali nei neuroni. Nonostante le resistenze opposte all'abbandono del dogma neurocentrico, una grande quantità di dati sperimentali raccolti negli ultimi trentanni ha contribuito a rimodellare il concetto di comunicazione sinaptica, considerando gli astociti, insieme ai terminali pre- e post- sinaptici, un elemento fondamentale della sinapsi tripartita. In altre parole, gli astrociti partecipano transversalmente al processamento dell'informazione nel cervello modulando sia la trasmissione sinaptica che differenti forme di plasticità. Questa nuova coscenza degli astrociti come elementi attivi nella fisiologia del cervello, suggerisce che essi possano essere coinvolti anche nelle patologie neurologiche. Molti studi hanno infatti rivelato che malfunzionamenti nella comunicazione tra neuroni ed astrociti sono direttamente legati a patologie quali il morbo di Alzheimer, il morbo di Parkinson, la sclerosi laterale amiotrofica e l'epilessia. L'obiettivo principale di questa tesi è stato capire come il rilascio di gliotrasmettitori, in particolare il glutammato, possa influenzare la generazione e la propagazione della scarica epilettica.
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Filipello, F. "MOLECULAR AND CELLULAR MECHANISMS IN ASTROCYTE-T CELL CROSS-TALK." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/232403.
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Migration of encephalitogenic T cells into the brain parenchima through the blood–brain barrier (BBB) is a crucial feature for initiating tissue injury in different neuroinflammatory diseases. The BBB is comprised of astrocyte processes and endothelial cells, which form the lumen of the brain microvasculature and help in maintaining immune quiescence through contact-dependent mechanisms as well as release of soluble factors. Activated CD4+ T cells may establish physical contacts with astrocytes, thereby reciprocally influencing cellular activity and functions. In addition, astrocytes and CD4 T cells may communicate through the secretion of soluble signaling molecules during contact. Among molecules secreted by astrocyte, ATP is a key messenger which can also signal to CD4 T cell through purinergic P2 receptors. Our results show that activated CD4+ T cells inhibit calcium oscillations in astrocytes through direct modulation of extracellular ATP levels. This effect correlated with the expression of plasma membrane ectonucleoside triphosphate diphosphohydrolase CD39, which is induced by contact of the activated T cell with astrocyte. In addition, T cell contact with astrocyte results in the upregulation of the ecto-5’-nucleotidase CD73, which converts AMP to adenosine. This effect was peculiar of T cell contact with astrocyte since it did not occur with microglia or peritoneal macrophages. Pharmacological inhibition of Ca2+ oscillations in astrocyte completely prevented CD73 induction on T cell, thus suggesting that a gliostrasmitter released by astrocyte in a Ca2+-dependent fashion might be responsible of this effect. Since degradation of ATP to adenosine by CD73 regulates BBB permeability and leukocytes infiltration into the brain this regulatory circuit might have important pathogenetic implications in multiple sclerosis and other neuroinflammatory conditions. Finally, functional characterization of T cell upon contact with astrocyte allowed us to assess a proinflammatory phenotype and Th17 skewing albeit with important differences, such as CD39 and CD73 expression, with respect to conventionally activated cells. Thus, we characterized an astrocyte specific signature of T cell activation, which might be important in the pathogenesis of neuroinflammatory disorders.
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Peters, Jennifer Lynn. "Astrocytes and the circadian clock: roles for calcium, light, and melatonin." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/3872.
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Melatonin is rhythmically synthesized and released by the pineal gland and, in some species, retina during the night and regulates many physiological and behavioral processes in birds and mammals. Chick diencephalic astrocytes express two melatonin receptor subtypes in vitro, and melatonin plays a role in regulating metabolic activity. We examined the role of glial cells in circadian function and asked if melatonin modulated glial functions within the retina and the brain. Calcium waves were potentiated by physiological concentrations of melatonin. Melatonin increased resting calcium levels and reduced gap junctional coupling among astrocytes at these same concentrations. Both mouse and chick diencephalic and telencephalic astrocytes express melatonin receptor protein. Nanomolar melatonin modulated astrocytic calcium waves of the mouse and chick diencephalon but not waves of the telencephalon. Mammalian intercellular calcium waves spread farther than avian calcium waves, and the nature of the spread of the waves differed between telencephalic and diencephalic mammalian astrocytes. These differences in propagation were abolished by melatonin. Using northern analysis, we identified period2, period3, cryptochrome1, cryptochrome2, clock, melanopsin and peropsin within chick diencephalic astrocytes. The clock genes cry1 and, per2 were expressed rhythmically in a LD cycle, but metabolic activity was not rhythmic. When cells were placed in constant darkness and rhythmically administrated melatonin, a robust rhythm in glucose uptake was induced without a coordinated clock gene rhythm, suggesting rhythmic clock gene expression and metabolic activity are separable processes. Melatonin affected visual function as assessed by electroretinogram. Circadian rhythms of a- and b-wave implicit times and amplitudes were observed. Melatonin (1 mg/kg and 100 ng/kg) decreased a- and b-wave amplitudes greater during the night than during the day and it increased a- and b-wave implicit times while 1 ng/kg melatonin had little to no effect over the saline controls. These data indicate that melatonin modulates glial intercellular communication, affects metabolic activity in astrocytes, and may play a role in regulating a day and night functional shift in the retina, at least partially through Müller glial cells. Thus, melatonin can regulate glia function and thereby, affect outputs of the vertebrate biological clock.
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Price, Toby. "SV40 T antigen as a method for immortalising human differentiated cells." Thesis, University of Sussex, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262300.
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Le, Douce Juliette. "Altération métabolique et déficit synaptique dans la maladie d'Alzheimer : rôle de la PHGDH astrocytaire." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066552/document.
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Les patients atteints de la MA souffrent d'altérations métaboliques et synaptiques précoces. Via la glycolyse et le cycle de Krebs, le métabolisme du glucose permet la production d'ATP, essentielle à l'activité et la plasticité synaptique. Contrairement aux neurones, les astrocytes utilisent majoritairement la glycolyse pour métaboliser le glucose. En plus de la production d'énergie, la glycolyse fournit les précurseurs indispensables à la synthèse de biomolécules comme la L-sérine. Cet acide aminé est produit à partir du glucose par la déviation du 3-phosphoglycérate (3PG), un intermédiaire glycolytique, via l'enzyme 3-phosphoglycérate déshydrogénase (PHGDH), exprimée spécifiquement dans les astrocytes. La L-sérine est le précurseur de la D-sérine, le principal co-agoniste des NMDAR nécessaires à l'activité et la plasticité synaptique.Nous avons utilisé des souris 3xTg-AD, un modèle développant une MA progressive, afin d'étudier si une altération de la production de L-/D-sérine pouvait contribuer à des déficits synaptiques.A 6 mois, lorsque les souris 3xTg-AD ne possèdent pas encore de plaques amyloïdes dans l'hippocampe, nous avons observé in vivo une diminution du métabolisme du glucose, de la concentration de L-sérine et des déficits synaptiques (LTP). L'expression locale de la PHGDH est aussi altérée. L'application de D-sérine restaure complètement les déficits de LTP chez les souris 3xTg-AD.Ces données supportent l'hypothèse qu'un déficit de production de L-sérine par les astrocytes médié par une diminution du flux glycolytique serait responsable de l'altération synaptique observée dans l'hippocampe des souris 3xTg-ADAn early alteration of both cerebral glucose metabolism and synaptic activity has been consistently described in Alzheimer's disease (AD) patients. Metabolism of glucose via glycolysis and the citric acid cycle produces ATP that is essential for synaptic activity and plasticity. In the brain, glucose is predominantly processed glycolytically into astrocytes and not by neurons. Beyond ATP production, a major function of aerobic glycolysis is to provide precursors to support macromolecular synthesis. L-serine, generated from glucose through diversion of the glycolytic intermediate 3-phosphoglycerate (3PG) into the phosphorylated pathway, is only produced in astrocytes by 3-phosphoglycerate dehydrogenase (PHGDH), selectively expressed in those glial cells. L-serine is the precursor of D-serine, the main co-agonist of synaptic NMDAR, required for synaptic activity and plasticity. We used 3xTg-AD mice, which develop a progressive pathology, to investigate whether a defective production of L-/D-serine contributes to early synaptic deficits in AD. We found that 3xTg-AD mice display early in vivo alterations of glucose metabolism, synaptic deficits (LTP) in the CA1 region and also lower concentration of L-serine. The local expression of PHGDH was significantly altered. Exogenous D-serine completely rescued LTP in 3xTg-AD mice. These data support the hypothesis that a deficit of L-serine synthesis by astrocytes likely mediated by a decreased glycolytic flux may be responsible for the synaptic alteration mediated by NMDAR in the hippocampus of 3xTg-AD mice
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Schmidt, Elke. "Investigation of spatiotemporal calcium transients in astrocytic soma and processes upon purinergic receptor activation using genetically encoded calcium sensors." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T011.
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Les astrocytes protoplasmiques de la matière grise corticale sont des cellules gliales dont les prolongements très fins et ramifiés sont en contact avec les éléments neuronaux pré- et post-synaptiques d’une part, et les vaisseaux sanguins d’autre part. Ils expriment plusieurs récepteurs des neurotransmetteurs, entre autres des récepteurs purinergiques dont l'activation facilite l’activité calcique astrocytaire et la libération de gliotransmitters (par exemple, le glutamate, le GABA, l'ATP, et la D sérine) qui régulent l’activité des neurones et des cellules gliales situées au voisinage. L’objectif de ma thèse était d’étudier in situ l’activité calcique des astrocytes et de leurs prolongements en réponse à l’application des agonistes purinergiques. Lors de ma thèse, j’ai tout d'abord testé la possibilité d’induire l’expression spécifique de gènes d’intérêt par les astrocytes corticaux de souris adultes par la technique de recombinaison Cre-LoxP. J’ai comparé les performances d’un virus adeno-associé de type 5 (AAV5) flexé (AAV5.FLEX.EGFP) et d’une souris qui exprime un indicateur calcique (GCaMP3) sous contrôle de la recombinase (souris Rosa-CAG-LSL-GCaMP3). L’injection d’AAV5.FLEX.EGFP dans le cortex d’une souris hGFAPcre n’a pas permis l’expression spécifique d’EGFP. La combinaison des souris exprimant le cre recombinase sous contrôle d’un promoteur sélectif des astrocytes (GLAST-CreERT2 et Cx30-CreERT2) avec le AAV5.FLEX.EGFP ou avec une lignée des souris Rosa-CAG-LSL-GCaMP3 permet l’expression spécifique des gènes d’intérêt (EGFP et GCaMP3) par les astrocytes corticaux. J’ai ensuite analysé l’activité calcique des astrocytes qui expriment GCaMP3. J’ai utilisé la microscopie biphotonique et enregistré l’activité calcique spontanée et évoquée par application d’agonistes purinergiques sur des tranches de cortex somatosensoriel primaire de souris adultes GLAST-CreERT2. L’activité calcique spontanée est complexe, généralement locale et désynchronisée, répartie dans les prolongements et la région somatique. Les régions actives ont été identifiées à partir d’une carte de corrélation temporale calculée en MATLAB, et leurs caractéristiques (amplitude, durée, position, fréquence) mesurées grâce à des routines établies sous IGOR. La fréquence et l’amplitude de l’activité calcique paraissent augmenter lors de l’enregistrement, ce qui suggère une sensibilité significative et une photoactivation des astrocytes, en imagerie biphotonique. La durée des impulsions laser modulerait ce phénomène. En présence d'adénosine (1-100 µM) et d’ATP (100 µM), et de façon marginale en présence d’un agoniste P2X7 non sélectif (BzATP 50-100 µM), une activité calcique synchronisée accrue est visible dans le soma et les prolongements astrocytaires en présence de tétrodotoxine qui bloque les potentiels d'action et minimise l’activité synaptique. Le mécanisme de ces réponses synchronisées reste à étudier. Aucun effet significatif n’a été observé en présence d’un agoniste spécifique P2Y1 (MRS2365 50 uM). Mon travail a permis le développement : i) de modèles murins pour l’adressage sélectif de protéines d’intérêt au niveau des astrocytes protoplasmiques ; ii) d’outils d’analyse des signaux calciques astrocytaires au niveau sub-cellulaire. Il a mis en évidence des limites possibles des protocoles standards d'enregistrement de l’activité calcique des astrocytes en imagerie biphotonique. Il confirme l’importance de l’ATP et de l’adénosine pour la signalisation astrocytaireGrey matter protoplasmic astrocytes are compact glial cells with highly branched processes, enwrapping synapses, and one or two endfeet contacting the blood vessels. Several neurotransmitter receptors are expressed by astrocytes, among them purinergic receptors. Upon activation of these receptors, intracellular calcium (Ca2+) transients can be induced, that, in turn, trigger gliotransmitter release (e.g. glutamate, GABA, ATP, D-serine) and participate in astrocyte-to-astrocyte signaling as well as in the communication between astrocytes and neurons or other glia. During my PhD work, I first implemented and validated several approaches for targeting transgene expression specifically to cortical astrocytes and employed them to study purinergic signaling in astrocytes. To achieve astrocyte-specific transgene expression, I used either floxed adeno-associated viral (AAV) vectors or a Cre-dependent mouse line and several mouse lines expressing the Cre recombinase under astrocyte-specific promoters. Intracerebral injections of a Cre-dependent AAV serotype 5 containing the ubiquitous CAG promoter and an enhanced green fluorescent protein (AAV5.CAG.flex.EGFP) in adult mice expressing Cre recombinase under the human glial fibrillary protein (hGFAP) promoter resulted in a non-astrocyte specific expression in the cortex. Combining inducible mouse lines expressing Cre recombinase under the glutamate aspartate transporter (GLAST) promoter with the same AAV vector resulted in a virtually astrocyte-specific expression of the reporter gene. As an alternative approach for astrocyte-specific transgene expression, we used a Cre-dependent mouse line expressing the genetically encoded Ca2+ indicator GCaMP3. Crossing this mouse line with the above described GLAST-CreERT2 mouse line or a Connexin30 (Cx30)-CreERT2 line led to selective GCaMP3 expression in cortical astrocytes. Second, I investigated both spontaneous and agonist-evoked Ca2+ transients in astrocytic processes, the investigation of which has presented a major challenge in earlier studies, due to the unspecific and weak labeling by membrane-permeable chemical Ca2+ indicators. Using the strategy developed in the first part of my work allowing an astrocyte-specific expression of the genetically encoded Ca2+ indicator GCaMP3. Using two-photon excitation fluorescence (2PEF) imaging in acute slices of the primary somatosensory cortex, I recorded Ca2+ transients in the astrocytic soma and processes. By aid of a custom-made MATLAB routine based on a temporal Pearson correlation coefficient, active regions could be identified in an unbiased manner. Evoked Ca2+ transients were quantified using custom IGOR routines. Spontaneous desynchronized Ca2+ transients occurred in the processes and rarely in the soma. Ca2+ signals appeared localized in distinct microdomains. Their frequency appeared to increase during long recordings of several hundred images, suggesting that fine astrocytes are vulnerable to photodamage under imaging conditions routine in 2PEF microscopy. The possibility to minimize photodamage, by varying the length of the femtosecond laser pulses is under investigation. Bath application of adenosine (1-100 µM) and adenosine-triphosphate (ATP, 100 µM), as well as the application of the non-selective P2X7 receptor agonist (2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate, BzATP, 50-100 µM), in the presence of tetrodotoxin to block neuronal action potentials, evoked synchronized Ca2+ rises in the soma and the processes of astrocytes. The effect of adenosine was dose-dependent. No significant effect of the specific P2Y1 agonist (MRS2365, 50 µM) was seen. Altogether, my work sets up a powerful and versatile toolbox for studying astrocytic Ca2+ signaling at the sub-cellular level. It also pinpoints possible limits of standard two-photon recording protocols to investigate the local Ca2+ signals in fine astrocytic processes
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Tyzack, Giulia. "Mechanisms underlying astrocyte mediated plasticity induced by signals of neuronal injury." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709045.
Full text
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Hlavac, Nora. "Attributes of Astrocyte Response to Mechano-Stimulation by High-Rate Overpressure." Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/98534.
Full textAbstract:
Blast neurotrauma represents a significant mode of traumatic injury to the brain. The incidence of blast neurotrauma is particularly high amongst military combat personnel and can be debilitating and endure clinically for years after injury is sustained. Mechanically, blast represents a unique and complex loading paradigm associated with compressive shock waves that propagate out from an explosive event and interact with the head and other organs through high-rate loading. When subjected to such insult, brain cells undergo characteristic injury responses which include neuroinflammation, oxidative stress, edema and persistent glial activation. These features of the injury have emerged as important mediators of the chronic brain damage that results from blast.
Astrocytes have emerged as a potential therapeutic target because of their ubiquitous roles in brain homeostasis, tissue integrity and cognitive function. This glial subtype has a characteristic reactive response to mechanical trauma of various modes. In this work, custom in vitro injury devices were used to characterize functional models of astrocyte reactivity to high-rate insult to study mechano-stimulation mechanisms associated with the reactive phenotype. The working hypothesis was that high-rate overpressure exposure would cause metabolic aberrations, cell junction changes, and adhesion signal transduction activation, all of which would contribute to astrocyte response and reactivity. Astrocyte cultures were exposed to a 20 psi high-rate overpressure scheme using an underwater explosion-driven device.
Astrocytes experienced dynamic energetic fluctuations in response to overpressure which were followed by the assumption of a classically defined reactive phenotype. Results indicated specific roles for cationic transduction, cell junction dynamics (gap junction and anchoring junctions) and downstream signal transduction mechanisms associated with adhesion alterations in onset of the astrocyte reactive phenotype. Investigation into adhesion signaling regulation by focal adhesion kinase in 2D and 3D cultures was also explored to better understand cellular reactivity as a function of extracellular environment. Additionally, another underwater in vitro device was built to study combination effects from overpressure and fluid shear associated with insult.
Overall, the combined studies offer multiple mechanisms by which to explore molecular targets for harnessing astrocytes' potential for repair after traumatic injury to the brain.PHD
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Muthukumar, Allie. "Astrocyte-Neuron Interactions Regulate Nervous System Assembly and Function: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/745.
Full textAbstract:
Astrocytes densely infiltrate the brain and intimately associate with synaptic structures. In the past 20 years, they have emerged as critical regulators of both synapse assembly and synapse function. During development, astrocytes modulate the formation of new synapses, and later, control refinement of synaptic connections in response to activity dependent cues. In a mature nervous system, astrocytes modulate synapse function through a variety of mechanisms. These include ion buffering, neurotransmitter uptake and the release of molecules that activate synaptic receptors. Through such roles, astrocytes shape the structure and function of neuronal circuits. However, how astrocytes and synapses reciprocally communicate during circuit assembly remains an unanswered question in the field. The vast majority of our understanding of astrocyte biology has come from studies conducted in mammals, where it is challenging to dissect molecular mechanisms with cell type specificity. Drosophila melanogaster is a less established model system for studying astrocyteneuron interactions, but its vast array of genetic tools and rapid life cycle promises great potential for precisely targeted manipulations. My thesis work has utilized Drosophila melanogaster to investigate the reciprocal nature of astrocyte-synapse communication. First, I characterized Drosophila late metamorphosis as a developmental stage in which astrocyte-synapse associations can be studied. My work demonstrates that during this time, when the adult Drosophila nervous system is being assembled, synapse formation relies on the coordinated infiltration of astrocyte membranes into the neuropil. Next, I show that in a reciprocal manner, neural activity can shape astrocyte biology during this time as well and impart long lasting effects on neuronal circuit function. In particular expression of the astrocyte GABA transporter (GAT) is modulated in an activity-dependent manner via astrocytic GABABR1/2 receptor signaling. Inhibiting astrocytic GABABR1/2 signaling strongly suppresses hyperexcitability in a Drosophila seizure model, vii arguing this pathway is important for modulating excitatory/inhibitory balance in vivo. Finally, utilizing the ease of the Drosophila system, I performed a reverse genetic screen to identify additional astrocyte factors involved in modulating excitatory-inhibitory neuronal balance.
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Muthukumar, Allie. "Astrocyte-Neuron Interactions Regulate Nervous System Assembly and Function: A Dissertation." eScholarship@UMMS, 2001. http://escholarship.umassmed.edu/gsbs_diss/745.
Full textAbstract:
Astrocytes densely infiltrate the brain and intimately associate with synaptic structures. In the past 20 years, they have emerged as critical regulators of both synapse assembly and synapse function. During development, astrocytes modulate the formation of new synapses, and later, control refinement of synaptic connections in response to activity dependent cues. In a mature nervous system, astrocytes modulate synapse function through a variety of mechanisms. These include ion buffering, neurotransmitter uptake and the release of molecules that activate synaptic receptors. Through such roles, astrocytes shape the structure and function of neuronal circuits. However, how astrocytes and synapses reciprocally communicate during circuit assembly remains an unanswered question in the field. The vast majority of our understanding of astrocyte biology has come from studies conducted in mammals, where it is challenging to dissect molecular mechanisms with cell type specificity. Drosophila melanogaster is a less established model system for studying astrocyteneuron interactions, but its vast array of genetic tools and rapid life cycle promises great potential for precisely targeted manipulations. My thesis work has utilized Drosophila melanogaster to investigate the reciprocal nature of astrocyte-synapse communication. First, I characterized Drosophila late metamorphosis as a developmental stage in which astrocyte-synapse associations can be studied. My work demonstrates that during this time, when the adult Drosophila nervous system is being assembled, synapse formation relies on the coordinated infiltration of astrocyte membranes into the neuropil. Next, I show that in a reciprocal manner, neural activity can shape astrocyte biology during this time as well and impart long lasting effects on neuronal circuit function. In particular expression of the astrocyte GABA transporter (GAT) is modulated in an activity-dependent manner via astrocytic GABABR1/2 receptor signaling. Inhibiting astrocytic GABABR1/2 signaling strongly suppresses hyperexcitability in a Drosophila seizure model, vii arguing this pathway is important for modulating excitatory/inhibitory balance in vivo. Finally, utilizing the ease of the Drosophila system, I performed a reverse genetic screen to identify additional astrocyte factors involved in modulating excitatory-inhibitory neuronal balance.