WorldCat Identities

Oliet, Stéphane H. R. 1965-

Overview
Works: 31 works in 55 publications in 2 languages and 472 library holdings
Genres: Conference papers and proceedings  Academic theses 
Roles: Editor, Speaker, Other, Thesis advisor, Author, Opponent
Publication Timeline
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Most widely held works by Stéphane H. R Oliet
Vasopressin and oxytocin : from genes to clinical applications by D. A Poulain( )

19 editions published in 2002 in English and held by 381 WorldCat member libraries worldwide

The articles comprising this volume were first presented at the World Congress on Neurohypophysial Hormones held in Bordeaux, France on September 8-12, 2001. This conference brought together more than 170 scientists from 18 countries who belong to the different fields of interest representing research in the hypothalamo-neurohypophysial system. Two neurohypophysial neurohormones, oxytocin and vasopressin, exert a variety of central and peripheral actions and thus involve different scientific domains, which too often, even today, do not always find the appropriate occasion to interact. This vol
Neuronal-glial anatomical plasticity in the hypothalamus by Stéphane H. R Oliet( Visual )

3 editions published in 2013 in English and held by 52 WorldCat member libraries worldwide

Osmoreception in rat supraoptic neurons by Stéphane H. R Oliet( )

3 editions published between 1994 and 1996 in English and held by 5 WorldCat member libraries worldwide

"The osmotic control of neurohypophysial hormone release is mediated by central and peripheral osmoreceptors which perceive changes in fluid osmolality. The mechanism underlying signal transduction in these structures, however, has remained obscure. Supraoptic neurons, which synthesize and secrete the neurohypophysial hormones, are themselves recognized to be osmoreceptors. Combined electrophysiological and micromorphometric measurements were therefore obtained in acutely isolated rat supraoptic neurons to determine the cellular basis for signal transduction in osmoreception. Osmotically-evoked changes in cell volume and a gadolinium-sensitive cationic conductance were found to be temporally and proportionally related. In agreement, cell-attached patch-clamp recordings revealed the presence of gadolinium-sensitive cationic channels modulated in response to osmotic stimuli. The mean closed time of these channels was found to increase as a function of changes in membrane tension mediated either by external osmotic perturbation, or by application of pressure inside the patch pipette. The ionic selectivity, density, mechanosensitivity, and pharmacological properties of these channels are consistent with an involvement in the mechanism underlying osmosreception in supraoptic neurons."--
Conséquences fonctionnelles de la plasticité anatomique sur la transmission synaptique dans le noyau supraoptique chez la rate allaitante by Richard Piet( )

2 editions published in 2003 in French and held by 3 WorldCat member libraries worldwide

During lactation, the supraoptic nucleus (SON), which is composed of magnocellular neurons, undergoes a reversible anatomical remodeling that includes a striking reduction in the glial coverage of its neurons. Since astrocytes play a major role in the uptake of glutamate and constitute a physical barrier to diffusion in the extracellular space, we have investigated whether this decrease in astrocytic coverage of SON neurons was affecting the clearance and diffusion of glutamate. Our data indicate that the glial coverage of neurons is indeed associated with a glutamate uptake deficiency and a facilitation of its diffusion within the tissue. Such alterations result in a reduction of the efficacy of excitatory synapses and a facilitation of glutamate-mediated intersynaptic cross talk in the SON. Therefore, the degree of astrocytic coverage of neurons appears as an important contributor to the regulation of synaptic and extrasynaptic transmission
Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease by Kelly Ceyzériat( )

1 edition published in 2018 in English and held by 2 WorldCat member libraries worldwide

Rôle des astrocytes dans le contrôle de l'activité des récepteurs NMDA et dans laplasticité synaptique à long terme dans le noyau supraoptique chez le rat by Aude Panatier( Book )

2 editions published in 2006 in French and held by 2 WorldCat member libraries worldwide

Increasing evidence indicates that beside pre- and postsynaptic neuronal elements, astrocyte is the third element of the synapse. Indeed, it can detect, integrate and modulate synaptic signals. My work focuses on the role of astrocytes in glutamatergic synaptic transmission and more precisely in NMDA receptor (NMDAR) activity. The NMDAR is a key player in excitatory transmission. I showed that NMDARs are responsible for the induction of long-term synaptic plasticity in hypothalamic supraoptic nuclei (SON). It is known that their activation depends on the binding of both, glutamate, and a co-agonist like glycine or D-serine. Interestingly, D-serine is synthezized and released by astrocyte. Thus, this amino acid offers a unique opportunity to test the influence of astrocytic coverage of synapses on glutamatergic synaptic transmission. To this end, I took advantage of the extensive reduction of astrocytic ensheathing of neurons and synapses that SON undergoes during lactation. By combining electrophysiological recordings with biochemistry and immunochemistry, I provided direct evidence that astrocytic D-serine is the only endogenous co-agonist of NMDARs in the SON. Thus, the activation of SON NMDARs requires the binding of glutamate and D-serine, but not glycine. Moreover, by comparing NMDAR activity under different astrocytic coverage of neurons and synapses, I found that astrocytes, by releasing D-serine at glutamatergic synapses, control not only the level of activation of synaptic NMDARs but also, the activity-dependence of long-term synaptic changes. Such a mechanism might be extended to all brain regions where D-serine is present. My work clearly identifies astrocytes as key players in signalling and storage of information in the brain
Sequential alteration of microglia and astrocytes in the rat thalamus following spinal nerve ligation by Lucie Blaszczyk( )

1 edition published in 2018 in English and held by 2 WorldCat member libraries worldwide

Dynamic and metabolic astrocyte-neuron interactions in healthy and diseased brain( Book )

1 edition published in 2016 in English and held by 2 WorldCat member libraries worldwide

Role of vSNAREs in post-synaptic AMPAR trafficking, glutamatergic transmisson and plasticity by May Bakr( )

1 edition published in 2020 in English and held by 1 WorldCat member library worldwide

Rôles des récepteurs kaïnate dans le noyau supraoptique de l'hypothalamus de rat by Valérie Bonfardin( )

1 edition published in 2009 in French and held by 1 WorldCat member library worldwide

Magnocellular neuroendocrine cells (MNCs) from the supraoptic nucleus (SON) of the hypothalamus synthesize and release the hormones oxytocin (OT) and vasopressin (VP). OT is involved principally in reproductive functions such as parturition and lactation, whereas VP plays a key role in body fluid and cardiovascular homeostasis. The release of OT and VP from the neurohypophysis is controlled by the electrical activity of hypothalamic MNCs, which is itself regulated by GABAergic and glutamatergic synaptic inputs. Presynaptic kainate receptors (KARs) exert a modulatory action on transmitter release in different structures of the central nervous system. This effect can be switched from facilitation to inhibition by an increased concentration of KAR agonists. KAR can also be present postsynaptically where they were shown to participate to the synaptic response in some brain regions. We have demonstrated for the first time that functional KARs were present on GABAergic and glutamatergic inputs as well as on SON neurons. GluR5-containing KARs differentially regulate glutamatergic transmission on OT and VP neurons. Indeed, applications of exogenous agonists of GluR5 induced opposite effects, a facilitatory effect on OT neurons and an inhibitory effect on VP neurons, the latter resulting from an indirect action mediated by postsynaptic GluR5-containing KARs on VP neurons. Thus, activation of these receptors induced the release of a retrograde messenger, probably dynorphin, which in turn act presynaptically to inhibit glutamate release. Regarding the modulation of GABAergic transmission in the SON, we here showed that the increased levels of ambient glutamate associated with the physiological withdrawal of astrocytic processes occuring during lactation could modify the activity of presynaptic KARs. We demonstrated for the first time that a physiological astrocytic plasticity modifies the mode of action of presynaptic KARs from ionotropic to metabotropic, thereby inversing their coupling with GABA release from facilitation into inhibition. The results obtained during my PhD have thus showed that KARs are present both pre-and post-synaptically on adult MNCs. Moreover, KARs differentially regulate OT and VP neurons, which suggest that KARs could play key roles in the regulation of their activity and in physiological processes in which MNCs are involved
Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms( )

1 edition published in 2014 in English and held by 1 WorldCat member library worldwide

Abstract Key points The mechanisms of osmotically induced vasopressin secretion from the hypothalamic magnocellular neurosecretory cells, which is crucial for body fluid homeostasis, are not yet fully understood. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses and might be involved in the regulation of vasopressin release in response to changes in osmolality. We found that ERK was dose-dependently activated (phosphorylated) in the rat osmosensitive forebrain regions, including magnocellular neurosecretory cells, by increases in osmolality induced by hypertonic solutions. Inhibition of ERK phosphorylation reduced hypertonically induced activation of osmosensitive forebrain neurones and vasopressin release. Our results identify ERK activation as a new element contributing to the osmoregulatory mechanisms of vasopressin release. Abstract Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK-immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of vasopressin release
Maturation morpho-fonctionnelle de la synapse fibre moussue/cellule pyramidale de CA3 dans l'hippocampe by Frédéric Lanore( )

1 edition published in 2010 in French and held by 1 WorldCat member library worldwide

The formation of synapses follows different steps including synaptogenesis and maturation. These different steps depend on coordinated pre- and post-synaptic assembly. Pre-synaptic proteins and ionotropic glutamate receptors play a central role in these processes. During my thesis, I have been interested in the implication of the presynaptic protein Bassoon in the maturation of the hippocampal mossy fiber to CA3 pyramidal cell glutamatergic synapses. This synapse constitutes an attractive model for the study of synaptic maturation because it follows several steps of defined morphological and functional maturation. Bassoon in one of the first protein present at newly formed synaptic contacts. By electrophysiological approaches, we showed that Bassoon is important for the organization of the active zone during the first two postnatal weeks.Kainate receptors play an important role in the regulation of network activity during postnatal development. However, the impact of kainate receptors activation on synaptic maturation is less known. I showed a delay in functional maturation of mossy fiber synapses in mice deficient for the GluK2 subunit of kainate receptors (GluK2-/-). To know if this delay is correlated to morphological alterations of this synapse, we setup in vivo lentiviral infections of membrane fluorescent protein (YFP) in mouse pups (P1-P2). Using confocal microscopy and 3D reconstruction, we described the morphological maturation of mossy fiber synapses. We were able to correlate functional and morphological maturation and our results also showed an impairment in the formation of mossy fiber synapses in GluK2-/-. Together, these data reveal the importance of synaptic activity and of the coordination of pre- and post-synaptic assembly during synaptic maturation
Super-resolution STED and two-photon microscopy of dendritic spine and microglial dynamics by Thomas Pfeiffer( )

1 edition published in 2017 in English and held by 1 WorldCat member library worldwide

Les changements des connections neuronales interviendraient dans la formation de la mémoire. J'ai développé de nouvelles approches basées sur l'imagerie photonique pour étudier (i) les interactions entre les microglies et les épines dendritiques, et (ii) le renouvellement des épines dans l'hippocampe in vivo. Ces deux phénomènes contribueraient au remodelage des circuits synaptiques intervenant dans la mémoire. (i) Les microglies sont impliquées dans de nouvelles fonctions en condition saine. J'ai examiné l'effet de la plasticité synaptique sur la dynamique morphologique des microglies, et sur leur interaction avec les épines. En combinant l'électrophysiologie et l'imagerie bi-photonique dans des tranches aigües de souris transgéniques, je démontre que la microglie intensifie son interaction physique avec les épines. Ainsi pour continuer l'étude de ces interactions et leur impact fonctionnel plus précisément, j'ai optimisé l'imagerie STED dans des tranches aigües. (ii) La plasticité structurale des épines est cruciale pour la mémoire, mais les connaissances à ce sujet dans l'hippocampe in vivo restent limitées. J'ai donc établi une technique d'imagerie chronique STED in vivo pour visualiser les épines dans l'hippocampe. Cette approche a révélé une densité double de celle reportée précédemment à l'aide de la microscopie bi-photonique. De plus j'ai observé un renouvellement des épines de 40% en 5 jours, représentant un taux important de remodelage synaptique dans l'hippocampe. Les approches d'imagerie super-résolutive permettent l'étude des interactions microglie-épine, et du renouvellement des épines hippocampiques avec une résolution inédite chez la souris vivante
Caractérisation de la transmission GABAergique dans le globus pallidus externe chez des modèles rongeurs des maladies de Parkinson et de Huntington by Marine Chazalon( )

1 edition published in 2015 in French and held by 1 WorldCat member library worldwide

The basal ganglia (BG) are a group of sub-cortical nuclei involved in motor, memory and cognitive functions. In the BG, the GABAergic external globus pallidus (GPe) holds a position of relay nucleus between the striatum (STR) and the sub thalamic nucleus within the indirect pathway of the BG. Modifications of rate and pattern of activity of this nucleus are known to be the electrophysiological signatures of Parkinson's (PD) and Huntington's diseases (HD). In PD, hyperactivity of the striato-pallidal (STR-GPe) pathway is thought to be responsible for the increase of the extracellular GABAergic concentrations in the GPe and participate to the hypoactivity of pallidal neurons observed in experimental Parkinsonism. In contrast, during HD, it is recognized that the hyperactivity of GPe neurons is due to the degeneration of striato-pallidal neurons and thus to the reduction of the main source of pallidal GABAergic inhibition. However, the molecular mechanisms involved in these modifications of pallidal activity are not well characterized. Therefore, using PD and HD animal models, the 6-OHDA rodents and the R6-1 transgenic mice respectively, we have performed molecular biology, immunohistochemistry and electrophysiological in vitro experiments in order to better understand the origin of GABAergic transmission alterations leading to changes in electrophysiological activity of GPe neurons into these two pathologies. My main results show the apparition of a tonic GABAergic inhibition due to a deficit of GABA uptake in PD and a early stage reduction of GABAergic synaptic transmission in HD. Altogether, these results suggest that alterations of GABAergic transmission contribute to the pathophysiology of PD and HD
Régulation du trafic des récepteurs AMPA et de la plasticité synaptique induite par les récepteurs P2X by Johan Pougnet( )

1 edition published in 2013 in French and held by 1 WorldCat member library worldwide

Les récepteurs ionotropiques AMPA (AMPAR) activés par le glutamate sont les principaux acteurs de la transmission synaptique excitatrice rapide du cerveau. Ils jouent également un rôle crucial dans les processus de plasticité synaptique, reconnus pour être à la base des fonctions cognitives. Les récepteurs canaux P2X sont activés par l'adénosine-5'-triphosphate (ATP) extracellulaire libéré par les neurones ou les cellules gliales. Ils sont exprimés dans le cerveau en périphérie des synapses glutamatergiques, où ils participent à l'excitabilité neuronale et modulent la transmission synaptique ainsi que la plasticité synaptique. Bien que la signalisation purinergique ait de multiples effets sur la transmission et la plasticité synaptique, la fonction des récepteurs P2X au niveau des synapses du cerveau reste à établir. Ici, nous montrons dans les neurones d'hippocampe en culture que l'activation des récepteurs P2X postsynaptiques par l'ATP exogène ou via la libération d'ATP endogène par les cellules gliales diminue l'amplitude des courants miniatures et évoqués des AMPAR postsynaptiques. En utilisant des approches d'électrophysiologie, de biochimie et d'imagerie en temps réel, nous démontrons que l'afflux de calcium passant par les canaux P2X déclenche l'internalisation des AMPAR par un mécanisme d'endocytose clathrine et dynamine dépendante. Cette diminution de surface altère par conséquent la transmission synaptique médiée par les AMPAR. Nous avons aussi démontré par des approches moléculaires et pharmacologiques la cascade de signalisation engagée dans l'altération du trafic des AMPAR de surface après activation des récepteurs P2X. Cette inhibition par les récepteurs P2X, serait dépendante de l'activation de kinases et des phosphatases qui régulent le niveau de phosphorylation des AMPAR. Nos travaux de recherche suggèrent ainsi, que les récepteurs postsynaptiques P2X jouent un rôle essentiel dans la régulation de l'expression de surface des AMPAR et régulent ainsi la force et la plasticité synaptique
Contrôle de l'activité des récepteurs NMDA par la D-sérine : rôle des récepteurs astrocytaires EphB3 et CB1 by Valentin Langlais( )

1 edition published in 2016 in French and held by 1 WorldCat member library worldwide

Astrocytes are key partners of neurons. In the hippocampus, and more particularly at CA3-CA1 synapses, by releasing D-serine, these glial cells regulate the activity of synaptic Nmethyl-D-aspartate (NMDA) receptors and thus synaptic memory, also known as long-term synaptic plasticity. Yet, the synaptic signal inducing D-serine release by astrocytes is still unknown. Based on interesting data from the literature we have investigated the role of the astrocytic receptors for ephrinB3 (EphB3) and endocannabinoids (CB1). To this end we used electrophysiological approaches on acute hippocampal slices of adult mice. In a first study, our data indicate on one hand that the activation of EphB3 receptors increases synaptic D-serine availability and in consequences the activity of synaptic NMDA receptor activity. On the other hand, inhibition of EphB3 receptors induces a decrease of synaptic NMDA receptor activity as well as the induction of the long-term potentiation (LTP; a form of long-term plasticity). Thus, EphB3-ephrinB3 interaction controls LTP induction through the availability of synaptic D-serine. In a second study, we used a transgenic model allowing the inhibition of CB1 receptors expression in astrocytes (GFAP-CB1-KO mice). We discovered that their deletion reduced synaptic D-serine availability. Our work shows that astrocytic CB1 receptors are necessary for LTP induction via this D-serine. All together, this PhD work reveals that astrocytic EphB3 and CB1 receptors regulate synaptic NMDA receptor functions through the control of D-serine availability
Étude clinique et neurobiologique de la réponse comportementale à l'agression aigüe systémique by Aurélien Mazeraud( )

1 edition published in 2017 in French and held by 1 WorldCat member library worldwide

Systemic insults trigger neuroendocrine, neurovegetative and behavioural responses. Amygdala is particularly involved in anxiety and fear but also in the generation of post-traumatic stress disorder (i.e. PTSD). Amygdala is part of the limbic system and modulates the neuroendocrine and the autonomous nervous system activity. Behavioural changes to critical illness has been poorly studied in ICU-admited patients, despite studies showing that non-adapted corticotropic axis or autonomic nervous system responses correlate with a higher mortality or organ failures. During their ICU stay, patients are at high risk of developing psychological (e.g. anxiety, depression or PTSD), and cognitive alterations (e.g. memory and executive functions) with a major impact on their long-term quality of life. Such alterations intensity is correlated with the severity of critical illness. Our present work aimed, on the one hand at assessing at ICU admission patients' anxiety and its prognostic value, and on the other hand, at characterizing the link between amygdalar activation and PTSD in a murine model of caecal ligation and puncture (i.e. CLP). 354 patients were included in our observational study (median age 63 [IQR 49-73], sex 137W/217M), from 3 Ile-De-France ICU between January 2014 and September 2016). Median anxiety was moderate according to both visual scale (4 [1-6]) and STAI questionnaire (43[32-53]). Half of participants declared (54%) feeling vulnerable; considered their state to be severe (67%) and feared to die (45%). One organ failure - mostly neurological, but also the need for mechanical ventilation, dialysis or vasopressive catecholamines during the first 7 days - was present in 157 (45%) patients. A STAI index ≥ 40 (OR 4.93 ; 95% CI[1.02 - 2.84]) was associated with the occurrence of an organ failure, even after adjusting for the day-1 SOFA score, the onset of a mechanical ventilation (OR 4.93, 95CI [2.9 - 9.4]), the Knaus score of prior pathologies severity (OC 2.01, 95CI [1.21 - 3.33]) and fear of death. (OR 0.55 [0.33 -0.92]). The latter significantly associating with a decreased risk of organ failure among patients with a severe acute pathology as defined by a IGS-2 >30 (58% vs. 37%). This study shows that evaluating early anxiety can prove useful in predicting patient aggravation risk in ICU, but also indicates that if its intensity positively predicts the onset of organ failures, the lack of perceived severity (lower fear of death) would also associate with an increased risk of failure. Our experimental study higlighted an early (i.e. 6H post CLP) and transitory activation of Central Amygdala (CeA) CAMK-II positive neurons, and delayed (i.e D15 post CLP) alterations in open field and fear-conditioning tests, respectively indicating an anxious behaviour and fear hypermnesia, both critical aspects of PTSD. Pharmacogenetic inhibition of CAMK-II neurons by viral transduction led to a decrease in aversive sepsis-induced hypermnesia. Administration of Levetiracetam, an antipeileptic drug, during the first 24h post-CLP led to a decrease in sepsis-induced mortality, in CAMK-II CeA neurons activation and in aversive memory. Amygdalar neuronal activation was also associated with microglial morphological alterations, partly prevented by levetiracetam, and reminiscent of alterations seen in septic shock autopsic samples. Our experimental work shows an increased activity in CAMK-II amygdalar neurons during early sepsis, potentially implicated in the onset of sepsis-induced anxiety and PTSD. this constitutes a plausible neuro-anatomical and neuro-biological background to our clinical study showing the prognostic interest of early anxiety assessment in ICU patients, as it positively correlates with both stress intensity and the misperception of danger
Super-resolution imaging reveals differential organization and regulation of NMDA receptor subtypes by Blanka Kellermayer( )

1 edition published in 2018 in English and held by 1 WorldCat member library worldwide

Résumé: Les récepteurs du glutamate de type NMDA (NMDAR) sont des canaux ioniques impliqués dans les phénomènes de plasticité de la transmission synaptique dans le système nerveux central, des mécanismes supposés être à la base du développement neuronal, de l'apprentissage et de la formation de la mémoire. Les NMDAR forment des tétramères à la membrane plasmique, constitués de deux sous-unités obligatoires GluN1 et deux sous-unités variables GluN2 (GluN2A-D) ou GluN3. Dans le prosencéphale, les récepteurs comportant les sous-unités GluN2A (GluN2A-NMDAR) et GluN2B (GluN2B-NMDAR) sont les plus abondants et présentent des profils d'expression différents au cours du développement, les GluN2B-NMDAR étant fortement exprimés aux stades précoces tandis que l'expression des GluN2A-NMDAR augmente progressivement au cours du développement postnatal. Des contributions relatives de ces deux sous-types majoritaires de NMDAR aux propriétés de signalisation distinctes dépendent directement les phénomènes de plasticité neuronale, tels que l'adaptation des synapses glutamatergiques et des circuits neuronaux excitateurs. Bien que la régulation moléculaire des NMDAR ait fait l'objet d'intenses recherches ces dernières décennies, la localisation précise de ces deux sous-types de récepteurs dans la membrane postsynaptique demeurait méconnue. Pour répondre à cette question, nous avons étudié la distribution des NMDAR à la surface de neurones d'hippocampe de rats en combinant deux techniques de microscopie de super-résolution - la microscopie de reconstruction optique stochastique directe (dSTORM) et la déplétion d'émission stimulée (STED) - permettant de dépasser la limite de résolution inhérente à la diffraction de la lumière. Ces techniques nous ont permis de mettre en évidence que les sous-types de récepteurs GluN2A- et GluN2B-NMDAR présentent une nano-organisation différente à la surface neuronale. En effet, ils sont organisés en structures nanoscopiques (nanodomaines) qui diffèrent en nombre, en surface et en morphologie, notamment au niveau des synapses. Au cours du développement, l'organisation membranaire des deux sous-types de NMDAR évolue, avec en particulier de profonds changements de distribution des GluN2A-NMDAR. De plus, cette organisation nanoscopique est impactée différemment par des modulations de l'interaction avec les protéines d'échafaudage à domaine PDZ ou de l'activité de la kinase CaMKII suivant le sous-type de NMDAR considéré. En effet, la réorganisation des GluN2A-NMDAR implique principalement des changements de nombre de récepteurs dans les nanodomaines sans modification de leur localisation, tandis que la réorganisation des GluN2B-NMDAR passe essentiellement par des modifications de localisation des nanodomaines sans changements du nombre de récepteurs qu'ils contiennent. Ainsi, les GluN2A- et GluN2B-NMDAR présentent des nano-organisations différentes dans la membrane postsynaptique, reposant vraisemblablement sur des voies de régulation et des complexes de signalisation distincts
Etude structure/fonction des récepteurs kaïnate et de leur modulation by Julien Veran( )

1 edition published in 2011 in French and held by 1 WorldCat member library worldwide

Glutamate released at excitatory synapses acts on ligand-gated ionotropic receptors which fall into three classes: NMDA, AMPA and kainate receptors.At hippocampal mossy fiber synapses onto CA3 pyramidal cells, KARs are present both at the pre- and postsynaptic levels. Postsynaptic KARs are composed of the GluK2, GluK4 and GluK5 subunits, whereas presynaptic KARs are thought to comprise the GluK2 and GluK3 subunits. The functional properties of GluK3 (and GluK2/GluK3) receptors set it apart from the other ionotropic glutamate receptors. In particular, its sensitivity to glutamate is the lowest of all known ionotropic glutamate receptors, due in large part to fast desensitization of receptors with one or two bound glutamate molecules. The low agonist sensitivity of this receptor raises questions about its relevance for synaptic function. Therefore, it is possible that endogenous modulators may potentiate its function.Among potential endogenous modulators of KAR function, we chose to address the role of zinc, because of the large amounts contained in mossy fiber terminals. Zinc is thought to be accumulated into synaptic vesicles, and is co-released with glutamate in the extracellular milieu during neuronal activity. Zinc has been reported to inhibit most of native and recombinant KARs. Despite the proposed role of at hippocampal mossy fiber synapses, although modulation of GluK3-containing KARs by zinc has not yet been addressed.In this study, we show that zinc greatly potentiates recombinant GluK3 receptor currents evoked by glutamate. Zinc markedly slows receptor desensitization and increases apparent affinity for glutamate. Crystallographic studies and analysis of chimeric GluK2/GluK3 KARs and of GluK3 bearing selected point mutations, allowed us to identify the zinc binding domain defined by D759, H762, Q756 and D730, and localized in a region forming the interface between two GluK3 subunits in an LBD dimer assembly. Based on these structure-function studies and on modeling of KAR activity, we show that zinc plays a very distinct role on GluK3-KARs by stabilizing the interaction between dimers of LBD thereby reducing desensitization.Given the proposed localization of GluK3 close to zinc containing synaptic vesicles, zinc may be an endogenous allosteric modulator for native GluK3-KARs, and its binding site a new pharmacological target
Relations entre les dyskinésies L-dopa induites et le récepteur D1 de la dopamine dans les neurones striataux : étude expérimentale et perspectives en thérapeutique by Amandine Berthet( )

1 edition published in 2010 in French and held by 1 WorldCat member library worldwide

Mes travaux de thèse concernent le rôle du récepteur D1 de la dopamine dans les dyskinésies L-dopa induites, effets secondaires extrêmement handicapants du traitement de la maladie de Parkinson. En condition de dénervation striatale mimant l'environnement de la maladie de Parkinson, le traitement chronique par la L-dopa entraine des altérations majeures du trafic intraneuronal et de la signalisation du récepteur D1 de la dopamine dans les principaux neurones cibles de la dopamine, les neurones épineux de taille moyenne du striatum. Il existe en particulier une hypersensibilisation des récepteurs D1 dans les neurones striataux, avec une abondance accrue à la membrane plasmique et une diminution du niveau d'expression de la protéine GRK6 (Protéine kinase des Récepteurs Couplés aux Protéines G 6), un des acteurs clefs des phénomènes de désensibilisation, en relation directe avec l'apparition des dyskinésies.C'est dans ce contexte que se situe mon travail de thèse qui a eu pour objectif de mettre à profit et/ou de développer différents modèles expérimentaux et outils « in vivo » et « in vitro ». Nous avons associé des techniques d'imagerie cellulaire et tissulaire à des approches comportementales, afin d'explorer certains des événements cellulaires et moléculaires à l'échelle du neurone striatal et des réseaux neuronaux, reliant le niveau d'expression du récepteur D1, sa compartimentation cellulaire, son trafic intraneuronal et les dyskinésies ou des conditions pharmacologiques équivalentes.Nous avons confirmé dans le modèle du rat lésé unilatéralement à la 6-OHDA, traité par la L-dopa et développant des mouvements anormaux analogues aux dyskinésies chez l'homme, que le récepteur D1 est anormalement abondant à la membrane plasmique des neurones du striatum, alors qu'il devrait être internalisé après stimulation par son ligand naturel, la dopamine. Nous avons mis en évidence que les mécanismes d'internalisation après stimulation par un agoniste restent néanmoins fonctionnels. Après administration de l'agoniste D1, chez les animaux dyskinétiques, l'abondance des récepteurs D1 augmente dans les compartiments notamment impliqués dans les mécanismes d'internalisation et de transport (vésicules) et de dégradation (corps multivésiculaires). Nous avons apporté une explication possible à cette abondance anormale et à ce défaut d'internalisation, en montrant qu'ils pourraient être dus à une hétérodimérisation entre les récepteurs D1 et D3. La co-activation des récepteurs D1 et D3 par la L-dopa favoriserait l'ancrage du récepteur D1 à la membrane plasmique des neurones striataux.Dans ce cadre, l'abord de l'étude de l'implication du protéasome dans la régulation de l'expression du récepteur D1 de la dopamine nous a semblé particulièrement important, sur la base des premières études soulignant l'implication de ce système catalytique dans le contrôle de l'activité et du métabolisme des récepteurs aux neurotransmetteurs. Nous avons révélé pour la première fois des liens entre l'activité catalytique du protéasome et la dynamique intraneuronale du récepteur D1 et plus particulièrement nous avons montré que son activité chymotrypsine-like est réduite de façon spécifique dans le striatum d'animaux dyskinétiques, comme une conséquence directe d'une déplétion en dopamine associée à une hyperstimulation dopaminergique.Nous avons testé en situation expérimentale une stratégie « thérapeutique » nouvelle en restaurant le mécanisme de désensibilisation homologue du récepteur D1 de la dopamine, par correction du déficit de la kinase GRK6 par transfert du gène correspondant via l'injection intrastriatale d'un vecteur lentiviral. Nous avons montré que cette approche permet de réduire considérablement la sévérité des dyskinésies dans les modèles rat et primate non-humain, analogues des dyskinésies chez l'homme et qu'elle restaure les effets thérapeutiques de la L-dopa. Ces effets sont la conséquence de la restauration des mécanismes de désensibilisation homologue : la surexpression de GRK6 entraîne l'internalisation spécifique des récepteurs D1. L'ensemble de nos résultats s'inscrit dans une démarche de recherche translationnelle menée depuis plusieurs années au laboratoire allant de la cellule au patient, avec pour but de transposer la compréhension des données expérimentales concernant les anomalies de l'expression du récepteur D1 de la dopamine en stratégies thérapeutiques dans les dyskinésies L-dopa induites. Nos investigations montrent qu'il est possible d'agir sur l'expression du récepteur D1 à la membrane plasmique des neurones striataux de manière indirecte, en manipulant trois co-activateurs de son métabolisme, pour espérer réduire « in fine » la sévérité des dyskinésies
 
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Alternative Names
Oliet, Stéphane, 1965-

Stéphane Henri Richard Oliet wetenschapper

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French (12)