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Novel regulatory mechanisms of the hippocampal inhibitory GABAergic synapse : involvement of the WNK signaling pathway and the conformational state of GABA-A receptors
No full textLe récepteur ionotrope de l'acide γ-aminobutyrique (GABAAR), perméable aux ions chlorures, est le principal récepteur neurotransmetteur médiateur de l'inhibition dans le cerveau des mammifères. La transmission GABAergique est soumise à une régulation complexe et multifactorielle. Non seulement façonnée par le cycle d'ouverture du GABAAR, qui dicte le passage entre ses conformations au repos, ouverte et désensibilisée, mais aussi par l'homéostasie des ions chlorure, laquelle détermine la polarité et l'efficacité de la transmission GABAergique, la transmission GABAergique repose aussi fortement sur le nombre de GABAARs présents à la membrane postsynaptique, localisée face aux sites présynaptiques de libération de GABA. Le nombre de ces récepteurs aux synapses est rapidement régulé par un mécanisme de "diffusion-capture", dans lequel les GABAARs alternent entre une diffusion rapide à la membrane plasmique extrasynaptique et un ralentissement suivi d'un confinement aux synapses. De fait, ce confinement et cette agrégation synaptique sont médiés par l'interaction entre les GABAARs et leur principale protéine d'échafaudage synaptique, la géphyrine. La régulation de la diffusion latérale des récepteurs est considérée comme le principal mécanisme d'ajustement du nombre de récepteurs aux synapses en réponse à la demande synaptique. De plus, l'activité neuronale régule cette diffusion latérale des GABAARs, notamment en contrôlant la liaison des récepteurs à la géphyrine par la modulation de la phosphorylation des récepteurs et/ou de la géphyrine en aval des cascades de kinases, influençant ainsi la conformation de ces protéines. Au cours de ma thèse, j'ai étudié la régulation dynamique des synapses GABAergiques dans l'hippocampe à travers la phosphorylation de la géphyrine et la conformation des récepteurs, en utilisant notamment des techniques de microscopie optique de pointe, telles que le suivi de particules individuelles (SPT), la microscopie de reconstruction optique stochastique (STORM) et la microscopie de localisation photo-activée (PALM), en recourant à des stratégies pharmacologiques et de mutagenèse dirigée in vitro et in vivo. Plus précisément, mes recherches suggèrent que l'organisation synaptique des GABAARs et de la géphyrine dans l'hippocampe est régulée dynamiquement et est médiée, entre autres, par la phosphorylation de la géphyrine via la voie de signalisation sensible au chlorure WNK/SPAK/OSR1, une cascade de kinases précédemment liée à l'homéostasie des ions chlorures et à la transmission inhibitrice. D'autre part, mes résultats indiquent que l'état de conformation des GABAARs impacte leur régulation dynamique et leur organisation au niveau de la synapse. En somme, mes travaux doctoraux apportent de nouvelles perspectives sur la régulation dynamique de l'organisation et de la fonction des synapses GABAergiques dans l'hippocampe mature des modèles murins.The chloride ion permeant ionotropic γ-aminobutyric acid receptor (GABAAR) is the principal neurotransmitter receptor mediating inhibition in the mammalian brain. The GABAergic GABAergic transmission is subjected to a complex and multifactorial regulation. Shaped by the gating cycle of GABAAR, which dictates the switch between their resting, open, and desensitized conformation and by chloride homeostasis which dictates the polarity and efficacy of the GABAergic transmission, the GABAergic transmission also relies heavily on the number of GABAARs present in the postsynaptic membrane opposite to presynaptic GABA-releasing sites. The number of GABAARs at synapses is rapidly regulated by a “diffusion-capture” mechanism wherein receptors alternate between rapid diffusion into the extrasynaptic plasma membrane and slowing down and confinement to the synapses. This confinement and synaptic aggregation are mediated by the interaction between GABAARs and their primary scaffolding protein at the synapse, gephyrin. Regulation of receptor lateral diffusion is considered the first mechanism for adjusting the number of receptors at synapses in response to synaptic demand. Neuronal activity regulates the lateral diffusion of GABAARs, particularly by controlling receptor binding to gephyrin through the modulation of receptor and/or gephyrin phosphorylation downstream of kinase cascades, which subsequently influences the conformation of these proteins. During my PhD, I have investigated the dynamic regulation of GABAergic synapses in the hippocampus through the lens of gephyrin phosphorylation and receptor conformation, using state of the art optical microscopy techniques, such as Single Particle Tracking (SPT), STochastic Optical Reconstruction Microscopy (STORM) or Photo-Activated Localization Microscopy (PALM), and relying on pharmacological and directed mutagenesis strategies in vitro and in vivo. More specifically, my research suggests that GABAergic synapses in the hippocampus are dynamically regulated, with modulation of GABAAR and gephyrin synaptic organization mediated by gephyrin phosphorylation through the chloride-sensitive WNK/SPAK/OSR1 signaling pathway, a kinase cascade previously linked to chloride homeostasis and inhibitory transmission. Additionally, my findings indicate that the conformation state of GABAARs impacts their dynamic regulation and organization at the synapse. Overall, my doctoral work provides new insights into the dynamic regulation of GABAergic synapses organization and function in the mature hippocampus of murine models
Nouveaux mécanismes de régulation de la synapse GABAergique inhibitrice de l’hippocampe : implication de la voie de signalisation WNK et de l’état de conformation des récepteurs GABA-A
No full textThe chloride ion permeant ionotropic γ-aminobutyric acid receptor (GABAAR) is the principal neurotransmitter receptor mediating inhibition in the mammalian brain. The GABAergic GABAergic transmission is subjected to a complex and multifactorial regulation. Shaped by the gating cycle of GABAAR, which dictates the switch between their resting, open, and desensitized conformation and by chloride homeostasis which dictates the polarity and efficacy of the GABAergic transmission, the GABAergic transmission also relies heavily on the number of GABAARs present in the postsynaptic membrane opposite to presynaptic GABA-releasing sites. The number of GABAARs at synapses is rapidly regulated by a “diffusion-capture” mechanism wherein receptors alternate between rapid diffusion into the extrasynaptic plasma membrane and slowing down and confinement to the synapses. This confinement and synaptic aggregation are mediated by the interaction between GABAARs and their primary scaffolding protein at the synapse, gephyrin. Regulation of receptor lateral diffusion is considered the first mechanism for adjusting the number of receptors at synapses in response to synaptic demand. Neuronal activity regulates the lateral diffusion of GABAARs, particularly by controlling receptor binding to gephyrin through the modulation of receptor and/or gephyrin phosphorylation downstream of kinase cascades, which subsequently influences the conformation of these proteins. During my PhD, I have investigated the dynamic regulation of GABAergic synapses in the hippocampus through the lens of gephyrin phosphorylation and receptor conformation, using state of the art optical microscopy techniques, such as Single Particle Tracking (SPT), STochastic Optical Reconstruction Microscopy (STORM) or Photo-Activated Localization Microscopy (PALM), and relying on pharmacological and directed mutagenesis strategies in vitro and in vivo. More specifically, my research suggests that GABAergic synapses in the hippocampus are dynamically regulated, with modulation of GABAAR and gephyrin synaptic organization mediated by gephyrin phosphorylation through the chloride-sensitive WNK/SPAK/OSR1 signaling pathway, a kinase cascade previously linked to chloride homeostasis and inhibitory transmission. Additionally, my findings indicate that the conformation state of GABAARs impacts their dynamic regulation and organization at the synapse. Overall, my doctoral work provides new insights into the dynamic regulation of GABAergic synapses organization and function in the mature hippocampus of murine models.Le récepteur ionotrope de l'acide γ-aminobutyrique (GABAAR), perméable aux ions chlorures, est le principal récepteur neurotransmetteur médiateur de l'inhibition dans le cerveau des mammifères. La transmission GABAergique est soumise à une régulation complexe et multifactorielle. Non seulement façonnée par le cycle d'ouverture du GABAAR, qui dicte le passage entre ses conformations au repos, ouverte et désensibilisée, mais aussi par l'homéostasie des ions chlorure, laquelle détermine la polarité et l'efficacité de la transmission GABAergique, la transmission GABAergique repose aussi fortement sur le nombre de GABAARs présents à la membrane postsynaptique, localisée face aux sites présynaptiques de libération de GABA. Le nombre de ces récepteurs aux synapses est rapidement régulé par un mécanisme de "diffusion-capture", dans lequel les GABAARs alternent entre une diffusion rapide à la membrane plasmique extrasynaptique et un ralentissement suivi d'un confinement aux synapses. De fait, ce confinement et cette agrégation synaptique sont médiés par l'interaction entre les GABAARs et leur principale protéine d'échafaudage synaptique, la géphyrine. La régulation de la diffusion latérale des récepteurs est considérée comme le principal mécanisme d'ajustement du nombre de récepteurs aux synapses en réponse à la demande synaptique. De plus, l'activité neuronale régule cette diffusion latérale des GABAARs, notamment en contrôlant la liaison des récepteurs à la géphyrine par la modulation de la phosphorylation des récepteurs et/ou de la géphyrine en aval des cascades de kinases, influençant ainsi la conformation de ces protéines. Au cours de ma thèse, j'ai étudié la régulation dynamique des synapses GABAergiques dans l'hippocampe à travers la phosphorylation de la géphyrine et la conformation des récepteurs, en utilisant notamment des techniques de microscopie optique de pointe, telles que le suivi de particules individuelles (SPT), la microscopie de reconstruction optique stochastique (STORM) et la microscopie de localisation photo-activée (PALM), en recourant à des stratégies pharmacologiques et de mutagenèse dirigée in vitro et in vivo. Plus précisément, mes recherches suggèrent que l'organisation synaptique des GABAARs et de la géphyrine dans l'hippocampe est régulée dynamiquement et est médiée, entre autres, par la phosphorylation de la géphyrine via la voie de signalisation sensible au chlorure WNK/SPAK/OSR1, une cascade de kinases précédemment liée à l'homéostasie des ions chlorures et à la transmission inhibitrice. D'autre part, mes résultats indiquent que l'état de conformation des GABAARs impacte leur régulation dynamique et leur organisation au niveau de la synapse. En somme, mes travaux doctoraux apportent de nouvelles perspectives sur la régulation dynamique de l'organisation et de la fonction des synapses GABAergiques dans l'hippocampe mature des modèles murins
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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