WorldCat Identities

Sans, Nathalie

Overview
Works: 18 works in 18 publications in 2 languages and 19 library holdings
Roles: Other, Opponent, Thesis advisor
Publication Timeline
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Most widely held works by Nathalie Sans
Analysis of Risk Factors for the Outcome of Primary Retinal Reattachment Surgery in Phakic and Pseudophakic Eyes by Lucia Brandenberg( )

1 edition published in 2003 in English and held by 2 WorldCat member libraries worldwide

Axonal homeostasis of VGLUT1 synaptic vesicles in mice by Xiaomin Zhang( )

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

Les vésicules synaptiques (VSs) sont essentielles pour la neurotransmission. Les recherches actuelles se focalisent sur la caractérisation de leur contenu en neurotransmetteurs, leur cinétique de libération, leur distribution et leur mobilité. Les VS ne sont pas présentes exclusievement en paquet dans les boutons présynaptiques mais sont echangées de façon dynamique avec le reste de l'axone dans un super-contingent (super-pool). Notre laboratoire a précédement montré que le transporteur vésiculaire de glutamate de type 1 (VGLUT1) jouerait un rôle dans la régulation du super-pool. Mon projet de thèse se focalise sur la mobilité des VS dans les axones. En premier lieu, j'ai généré une souris gain de fonction VGLUT1mEos2 afin d'étudier la mobilité des VSs et de mieux caractériser le super-pool. Ensuite j'ai engagé une étude des relation entre la structure de VGLUT1 et ses fonctions afin d'identifier les signatures moléculaires responsable de la régulation de la taille du super-pool. J'ai identifié le second motif poly-proline à l'extremité C-terminale de VGLUT1 comme étant nécessaire et suffisante pour induire une diminution de la taille du super-pool des VSs. Pour conclure mes travaux de thèse ont contribué à la compréhension du rôle de VGLUT1 dans la régulation de la mobilité des VSs et à fournir les outils nécessaires pour de futures investigations concernant la physiologie du super-pool
Impact of open channel blockers on the surface dynamics and organization of NMDA receptors by Alexandra Fernandes( )

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

N-Methyl-D-Aspartate glutamate receptors (NMDAR) are key actors of excitatory synaptic transmission, synaptic plasticity and higher brain functions such as memory formation and learning. As a consequence, NMDAR dysfunctions are associated to pathological states and high investments have been made to develop modulators of NMDAR activity for clinical applications. While some NMDAR antagonists such as ketamine (anesthetic, antidepressant) or memantine (prescribed as a treatment for Alzheimer's disease) have proven of great medical value, their clinical use is often limited by severe adverse effects (e.g. psychotic-like states induced by ketamine) and several questions regarding their action mode - including why some antagonists exhibit psychoactive properties when others do not - remain unanswered. Accumulating evidence suggests that beyond their channel function, physiological and pathological NMDAR signaling may involve non-canonical pathways independent from ion flux. Using a combination of epifluorescence, FRET-FLIM, biochemistry and single molecule localization microscopy approaches, we investigated the impact of competitive (D-AP5, CPP) and uncompetitive (MK-801, ketamine, memantine) NMDAR antagonists on the properties, redistribution and subsynaptic organization of surface NMDAR and their cytosolic partners in hippocampal neurons. We found that while all antagonists produce comparable inhibition of NMDAR ionotropic activity, exposure to the psychotomimetic blockers MK-801 and ketamine selectively triggers changes in the conformation of NMDAR. Interestingly, these conformational rearrangements were associated with a decreased surface diffusion and an increased residency time of receptors at synapses, suggesting MK-801 and ketamine binding possibly enhance NMDAR synaptic anchoring. Although drug exposure (1h) did not change the overall receptor abundance at excitatory synapses, super-resolution imaging revealed profound and antagonist-specific nanoscale reorganizations of synaptic NMDAR clusters, with exposure to the competitive antagonist D-AP5 causing a reduction in the size and an increase in the density of receptor nanodomains while inhibition by the uncompetitive psychotomimetic blockers MK-801 and ketamine triggered an enlargement of receptor nanodomains, and exposure to memantine prompted the fragmentation of these nanodomains. Moreover, we found that MK-801 and ketamine selectively enhanced the mobility of Ca2+/calmodulin-dependent protein kinase II (CaMKII) within dendritic spines through an action mode that relies on the direct interaction between both partners, suggesting that drug-induced receptor redistributions may impact the intracellular dynamics and organization of downstream signaling partners of NMDAR. Altogether, our results provide evidence that besides inhibition of ion fluxes through the receptors, competitive and uncompetitive antagonists have a different impact on NMDAR surface dynamics and subsynaptic organization, and suggest that the psychoactive blockers MK-801 and ketamine may act on receptor function through non-canonical rearrangements in the organization of NMDAR signaling complexes
Rôles physiologiques et pathologiques de la protéine précurseur amyloïde à la présynapse by Tomàs Jordà Siquier( )

1 edition published in 2021 in English and held by 1 WorldCat member library worldwide

Role of Scribble1 in hippocampal synaptic maturation, bidirectional plasticity and spatial memory formation in mice by Muna Hilal( )

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

Spatial memory formation is a complex process that transforms newly-acquired information into long-lasting and solid memories. Molecularly, these phenomena rely on the expression of two opposite forms of synaptic plasticity; long-term potentiation (LTP) and long-term depression (LTD). LTP/LTD induction relies on a fine balance between Ca2+-sensitive kinases and phosphatases that activate specific pathways of either LTP or LTD, respectively. This regulation also involves downstream interactions between receptors and highly specialized scaffold proteins, at the PSD. Scribble1 (Scrib1) is a scaffold protein that belongs to the LAP (leucine-rich repeats and PDZ domains) protein family, with 16 leucine rich repeats and 4 PDZ (PSD-95/Dlg/ZO-1) domains. Here, we developed conditional knock-out mice with a complete loss of Scrib1 expression in the major neurons of the postnatal forebrain, including hippocampal excitatory neurons, using the Cre-Lox system (Scrib1f/f,CaMKII-cre). Scrib1f/f,CaMKII-cre presented altered morphology of apical dendrites but intact spine density and spine morphology in the CA1 region. Functionally, we found increased number of silent (non-functional) synapses that decreases the number of active synapses in Scrib1f/f,CaMKII-cre CA1 neurons leading to a global decrease in basal glutamatergic synaptic transmission at CA3-CA1 synapses compared to Scrib1f/f synapses. Scrib1f/f,CaMKII-cre synapses displayed enhanced LTP but were unable to express LTD or long-term depotentiation. More strikingly, LTD-inducing protocols generated LTP in Scrib1f/f,CaMKII-cre synapses. Molecularly, we revealed a direct interaction between Scrib1 and the phosphatase PP2A that signals LTD at the synapse. Moreover, we found that the absence of Scrib1 results in a reduction of synaptic PP2A levels in Scrib1f/f,CaMKII-cre mice. This probably leads to a decrease in PP2A signaling pathway activation which favors the competing pathway downstream CaMKII resulting in LTP induction instead of LTD in Scrib1f/f,CaMKII-cre mice. On the cognitive level, we found that spatial learning was slower and inflexible in Scrib1f/f,CaMKII-cre compared to Scrib1f/f mice. Short-term spatial memory was intact while long-term memory was impaired. These results argue for an important role of Scrib1 in spatial memory consolidation. We here report that Scrib1 is important for appropriate neuronal shaping and wiring of CA1 neurons as well as functional conversion of silent synapses into active ones. Importantly, it allows bidirectional synaptic plasticity through interaction with PP2A and modulates long-term spatial memory formation
Rôle du microARN miR-124 dans la plasticité homéostatique via le contrôle de l'expression de la synaptopodine et des récepteurs AMPA dans les neurones de l'hippocampe by Sandra Dubes( )

1 edition published in 2019 in French and held by 1 WorldCat member library worldwide

Synaptic scaling is a form of homeostatic plasticity where synapses adjust their own efficacy to compensate for normal or pathological variations in neuronal activity such as neurodegenerative disorders or sensory deprivation after a lesion. In a well-established paradigm, the chronic application of tetrodotoxin (TTX) in primary neurons, to block presynaptic action potential propagation, induces a significant upscaling of miniature excitatory postsynaptic currents mediated-AMPA receptors. Numerous regulators of this plasticity have been identified including microRNAs (miR), which are small endogenous non-coding RNAs, inhibiting protein translation by binding to mRNA targets. This led us to hypothesize that the most highly expressed microRNA in the brain, miR-124, could be an important regulator of homeostatic scaling by controlling the expression of synaptopodin, a structural protein of dendritic spines playing a crucial role in homeostatic plasticity.By combining qRT-PCR, immunocytochemistry and in vitro electrophysiology approaches, first we showed that a global 48hrs TTX treatment in hippocampal primary neurons led to a decrease in miR-124 level and an increase in the expression of synaptopodin and synaptic AMPA receptors containing the GluA2 subunit which is another miR-124 target. Moreover, we observed that the synaptic accumulation of AMPA receptors and synaptopodin could be synapse-specific by expressing the tetanus toxin to block the activity of individual presynapses, which suggested a local homeostatic regulation. Importantly, we found that overexpressing miR-124 or inhibiting its interaction with synaptopodin or GluA2 mRNAs blocked the synaptic homeostatic response. In addition, FRAP experiments suggested that synaptopodin controlled AMPA receptor trafficking at the membrane by probably retaining them in dendritic spines, which could explain its role during homeostatic plasticity
L'interactome de Scrib1 et son importance pour la plasticitè synaptique & les troubles de neurodéveloppement by Vera Margarido Pinheiro( )

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

The brain is made up of billions of nerve cells, or neurons. Neurons communicate with each other through functionally distinct structures - the axon and the dendrite - which are able to release and receive an electrical or chemical signal from a pre- to a post-synaptic compartment, respectively. We focused our study on hippocampal neurons synapses, which ultimately underlie high-order brain functions, such as learning and memory. In particular, we studied the development and maintenance of dendritic spines, whose changes in morphology are intimately correlated with synaptic plasticity, or the ability to respond to synaptic activity. Dendritic spines originate from motile dendritic filopodia, which mature into spines following axonal contact. The filopodia-to-spine transition involves a plethora of molecular actors, including glutamate receptors, scaffold proteins and the actin cytoskeleton, able to receive, transmit and integrate the pre-synaptic signal. The spatial and temporal coordination of all these molecular components throughout the formation and maturation of a synapse remains, however, unclear. Scribble1 (Scrib1) is planar cell polarity protein (PCP) classically implicated in the homeostasis of epithelial tissues and tumour growth. In the mammalian brain, Scrib1 is a critical scaffold protein in brain development and function. The main goal of this work was, therefore, to investigate the molecular mechanisms underlying Scrib1 role in synapse formation and maintenance. In a first part, we depict the importance of Scrib1 PDZ-dependent interactions on glutamate receptors trafficking as well as bidirectional plasticity signalling pathway underying spatial memory. In a second part, we focus on the functional consequences of a recently identified autism spectrum disorder (ASD) mutation of Scrib1 on neuronal morpholgy and function. We demonstrated that Scrib1 regulates dendritic arborization as well as spine formation and functional maintenance via an actin-dependent mechanism, whose disruption might underlie the ASD phenotype. Taken altogether, this thesis highlights the PCP protein Scrib1 as key scaffold protein in brain development and function, playing a plethora of roles from the subcelular to the cognitive level
Transport intracellulaire des récepteurs AMPA et régulation par leurs protéines associées by Caroline Bonnet( )

1 edition published in 2021 in French and held by 1 WorldCat member library worldwide

Learning and memory rely on synaptic plasticity events during which the neuron modulates the efficiency of synaptic transmission. These events require a strict spatial and temporal control of the number of alpha-amino-3-hydroxy-5-méthyl-4-isoxazolepropionate receptors (AMPAR) at the post-synaptic plasma membrane (PM), and more importantly at the synapse. This control is a challenge for neurons in which the synapse can be localized hundred of micrometers away from the cell body and the nucleus where the genes are transcribed. The trafic and localisation of AMPAR is ensured by a complex cooperation between different mechanisms : intracellular transport (IT) of neosynthetized receptors to the PM, their diffusion at the PM and stabilization at the post-synapse or their recycling during which receptors are endocytosed and degraded or inserted again at the PM. The IT of neosynthetized receptors is a major contributor in the increase of AMPAR observed at the synapse during long term potentiation (LTP). The receptors mature in the different compartments of the secretory pathway and are transported in vesicles to the PM. The IT is difficult to image as it is composed of fast small vesicles of low contrast and that are impossible to distinguish from those containing recycled receptors. Thanks to a molecular tool allowing the retention of AMPAR in the endoplasmic reticulum combined with video-microscopy, our lab showed that the IT of GluA1 has stable characteristics in basal conditions. This IT is regulated by the Ca2+ concentration that varies after LTP induction, like in the late phase during which the number of vesicles and their speed are increased. It is also modulated by point-mutations of phosphorylation sites of AMPAR C-terminal domain (CTD).Our objective was to provide insight in the molecular mechanisms that govern this regulation. AMPAR have many interactors, including auxiliary proteins, membrane proteins that modulate their properties and trafficking. Gamma8, the most abundant auxiliary protein of the hippocampus, has a major role for LTP expression. The IT we observed in Gamma8-KO mice neurons is decreased compared to the WT, both in terms of number of vesicles and speed, while the time they spent in pause is increased. Our data suggest that Gamma8 participates in GluA1 IT.AMPAR also interact with cytosolic proteins via their CTD. GluA1 has two known cytosolic interactors : 4.1N and SAP97. The interaction with 4.1N is governed by two phosphorylations. 4.1N is involved in the exocytosis of the receptor especially during LTP. SAP97 is involved in the exit of the Golgi apparatus and is associated with the molecular motor MyoVI. In addition of its role in exocytosis, our data suggest that 4.1N regulates GluA1 IT during LTP but not in basal conditions. Indeed, after LTP induction, the vesicles containing the S816A S818A mutant that doesn't bind 4.1N show decreased speeds. Conversely, SAP97 regulates the IT in basal conditions by controlling the number of vesicles budding from the Golgi apparatus and by modulating their speed, a regulation that could be maintained after LTP induction.The most abundant AMPAR are GluA1/GluA2 heteromers. We characterized the IT of the GluA2 subunit and found that it exhibits the same characteristics as GluA1. GluA2 binds other proteins that might regulate the IT during activity, but their effect need to be determined. We propose that the IT of AMPAR is strongly modulated by its auxiliary proteins and cytosolic interactors of its CTD
L'astrocyte, intégrateur et régulateur de l'activité synaptique excitatrice dans des conditions physiologiques et pathologiques. by Dylan Pommier( )

1 edition published in 2019 in French and held by 1 WorldCat member library worldwide

Les données accumulées au cours des deux dernières décennies ont montré que l'astrocyte joue un rôle clé dans la régulation de la transmission synaptique. Cela est dû à sa capacité à détecter, via des récepteurs, et réguler, via la libération de gliotransmetteurs, la transmission synaptique. Cependant, les astrocytes deviennent réactifs dans des conditions pathologiques comme la maladie d'Alzheimer et la régulation de l'activité neuronale par ces cellules est susceptible d'être altérée.L'objectif principal de cette thèse est d'étudier le rôle de l'astrocyte en tant qu'intégrateur et modulateur de la transmission synaptique dans des conditions physiologique et pathologique.Premièrement, nous avons montré qu'un astrocyte est capable de détecter et d'augmenter la transmission synaptique de base au niveau d'une synapse chez des rats jeunes. On ignore si cette régulation est toujours présente chez les adultes et si elle est affectée par l'activité synaptique des synapses voisines présentes dans le même domaine astrocytaire. En utilisant l'imagerie STED et des enregistrements électrophysiologiques sur des tranches d'hippocampes de rats adultes, nous montrons ici que la voie de régulation décrite précédemment est également présente chez les adultes. En effet, les astrocytes détectent la transmission glutamatergique de base au niveau de synapses individuelles par le biais des mGluR5 et l'augmente en libérant des purines qui activent les récepteurs présynaptiques A2A. Plus important encore, nos données suggèrent fortement qu'un astrocyte est capable d'adapter sa régulation de la transmission glutamatergique en fonction du nombre de synapses activées dans son domaine. Lorsque le nombre d'afférences activées est faible, les astrocytes facilitent l'efficacité synaptique par un mécanisme dépendant des purines. Fait intéressant, ce processus n'est plus présent lorsqu'un plus grand nombre d'afférences est activé, ce qui suggère que les astrocytes sont capables d'intégrer différemment les informations entrantes et d'adapter leur réponse en termes de libération de purine.Deuxièmement, des études sur des modèles de la maladie d'Alzheimer ont rapporté que plusieurs fonctions astrocytaires, comme leur capacité à réguler la transmission synaptique, étaient perturbées. Cependant, la contribution de la réactivité astrocytaire dans cette pathologie reste méconnue et débattue du fait que les modifications rapportées dans ces études peuvent être bénéfiques et/ou néfastes pour les neurones. En effet, les astrocytes réactifs présentent une hétérogénéité morphologique, moléculaire et fonctionnelle qui peut expliquer leurs effets controversés dans cette pathologie. Pour comprendre comment la réactivité astrocytaire contribue à la maladie d'Alzheimer et trouver des voies thérapeutiques, il est essentiel de développer une nouvelle stratégie qui module efficacement tous les types d'astrocytes réactifs. Ici, nous avons utilisé des approches in vivo visant spécifiquement les astrocytes et identifié la voie JAK2/STAT3, comme étant nécessaire et suffisante pour l'induction et le maintien de la réactivité astrocytaire. La modulation de cette cascade par approche virale contrôle efficacement plusieurs caractéristiques morphologiques et moléculaires de la réactivité. De plus, son inhibition chez des modèles murins de la maladie d'Alzheimer améliore des caractéristiques pathologiques clés en réduisant les dépôts amyloïdes et en améliorant l'apprentissage spatial. En combinant l'approche virale avec des enregistrements électrophysiologiques, notre équipe a montré que réduire la réactivité astrocytaire en inhibant la voie JAK2/STAT3 rétablit les déficits de transmission synaptique et de plasticité observés chez un modèle 3xTg de la maladie d'Alzheimer. En conclusion, la cascade JAK2/STAT3 est un régulateur principal de la réactivité astrocytaire in vivo. Son inhibition offre de nouvelles opportunités thérapeutiques pour la maladie d'Alzheimer
Visualisation et perturbation de la dynamique spatio-temporelle de l'endocytose by Morgane Rosendale( )

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

The embryonic development of hindbrain respiratory networks is unaffected by mutation of the planar polarity protein Scribble( )

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

Highlights: Brainstem anatomy is drastically disrupted in the circletail (Scribble) mutant. Despite profound neural tube defects respiratory networks settle normally at their expected position in the hindbrain. In Scrib mutants respiratory neurons form functional rhythmogenic neuronal assemblages. The embryonic development of the central respiratory command is independent from the PCP component Scribble. Abstract: The central command for breathing arises mainly from two interconnected rhythmogenic hindbrain networks, the parafacial respiratory group (pFRG or epF at embryonic stages) and the preBötzinger complex (preBötC), which are comprised of a limited number of neurons located in confined regions of the ventral medulla. In rodents, both networks become active toward the end of gestation but little is known about the signaling pathways involved in their anatomical and functional establishment during embryogenesis. During embryonic development, epF and preBötC neurons migrate from their territories of origin to their final positions in ventral brainstem areas. Planar Cell Polarity (PCP) signaling, including the molecule Scrib, is known to control the developmental migration of several hindbrain neuronal groups. Accordingly, a homozygous mutation of Scrib leads to severe disruption of hindbrain anatomy and function. Here, we aimed to determine whether Scrib is also involved in the prenatal development of the hindbrain nuclei controlling breathing. We combined immunostaining, calcium imaging and electrophysiological recordings of neuronal activity in isolated in vitro preparations. In the Scrib mutant, despite severe neural tube defects, epF and preBötC neurons settled at their expected hindbrain positions. Furthermore, both networks remained capable of generating rhythmically organized, respiratory-related activities and exhibited normal sensitivity to pharmacological agents known to modify respiratory circuit function. Thus Scrib is not required for the proper migration of epF and preBötC neurons during mouse embryogenesis. Our findings thus further illustrate the robustness and specificity of the developmental processes involved in the establishment of hindbrain respiratory circuits
Rôle de Scribble1 dans la formation des synapses glutamatergiques et le trafic des récepteurs NMDA by Nicolas Piguel( )

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

One of the most studied and more important synapse is the glutamatergic excitatory synapse, which dysfunctions lead to brain pathologies. In the hippocampus, the most represented synapses are glutamatergic synapses using glutamate as neurotransmitter. Postsynaptic structures, such as dendritic spines, concentrate many glutamate receptors, adhesion proteins and scaffold proteins bridging receptors to molecular cascades and intracellular actin cytoskeleton. The morphology of the dendritic spine and the number of glutamate receptors at the surface of the spine are key-elements in synaptic transmission, such as of long-term potentiation (LTP). In this study, I identify Scribble1 as an important regulator of NMDA receptors trafficking. Scribble1 is well known for its roles in cell polarity, division and migration processes. First, I show that Scribble1 gain- and loss-of-function affect the number and morphology of spines, as well as the actin polymerization. Next, I showed that Scribble1 interacts directly with the NMDA receptor and stimulates its recycling to the membrane. Finally, in immature neuron, Scribble1 is involved in axon growth cone migration. In a Scribble1 mutant animal model, circletail, we observed disruption of synaptic transmission and memory and social performance defects, compatible with a role of the protein in central nervous system function
Dynamique d'échange de la dynamine mesurée dans les cellules vivantes pendant la formation de vésicules d'endocytose by Léa Claverie( )

1 edition published in 2019 in French and held by 1 WorldCat member library worldwide

L'endocytose dépendante de la clathrine (EDC), c'est-à-dire la formation de vésicules recouvertes de clathrine (VRC) à partir de la membrane plasmique, est un processus essentiel dans les cellules eucaryotes. Au cours de l'EDC, la GTPase dynamine est recrutée au cou de la VRC naissante où elle s'oligomérise en hélice. Les changements de conformation induits par l'hydrolyse du GTP catalysent la scission du cou vésiculaire. Ce processus a été étudié en détail par reconstitution in vitro sur des tubules membranaires, mais il doit être établi dans des cellules vivantes, où les interactions de la dynamine avec d'autres protéines comme l'amphiphysine sont critiques. L'imagerie TIRF (Total Internal Reflection Fluorescence) avec le protocole pH pulsé (ppH) sur cellules vivantes permet la détection de la formation de VRC avec une résolution spatiale (~100 nm) et temporelle (2 s) élevée. Ce protocole a révélé que la dynamine présente un recrutement biphasique aux puits recouverts de clathrine (PRC) en maturation avec un pic au moment de la scission mais les paramètres de son recrutement dans les cellules vivantes restent peu clairs. Pour déterminer ces paramètres, j'ai utilisé des techniques d'imagerie sur cellules vivantes pour étudier le recrutement de la dynamine à l'échelle globale et à l'échelle de la molécule unique lors de perturbations aiguës de sa fonction. Mes résultats de thèse ont montré que la dynamine est recrutée à la membrane plasmique, diffuse à l'extérieur des PRC et y est transitoirement piégée. De plus, j'ai déterminé avec des dynamines mutées (1) que le domaine PRD de la dynamine est crucial pour son recrutement aux PRC ; (2) que le domaine PH est important pour la scission vésiculaire mais par pour son recrutement aux PRC ou à la membrane plasmique. Enfin, j'ai observé que la dynamine s'échange en permanence avec un pool extra-PRC, ce qui permettrait son recrutement ultérieur par l'ajout de nouveaux sites de liaison et sa capacité à rétrécir le cou des vésicules suite à l'hydrolyse du GTP. En conclusion, ces données suggèrent qu'aux PRC, les molécules de dynamine (1) sont constamment échangées ; (2) diffusent à des taux similaires tout au long du processus de formation, maturation et scission des vésicules; et (3) l'activité GTPase de la dynamine contribue à la maturation et à la scission des VRC
Rôle de la signalisation de la polarité cellulaire planaire dans les processus mnésiques by Benjamin Robert( )

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

Planar cell polarity (PCP) signaling is an evolutionary conserved pathway known to play a crucial role in the establishment of tissue polarity via a regulation of cytoskeleton dynamics. PCP signaling is essential during critical developmental stages, such as gastrulation or neurulation, to shape tissues and organs, and disruption of core PCP genes in mammals leads to severe malformations and neonatal death. Van Gogh-like 2 (vangl2) is one of the core PCP genes coding for a transmembrane protein, and its mutation leads to a failure of the neural tube closure in mammals, including humans. It has also been suggested that Vangl2 plays a role in axonal guidance, dendritic arborization of hippocampal neurons and dendritic spines number. I showed that Vangl2 protein is enriched in the hippocampus in the adult stage, precisely in the dentate gyrus (DG) and CA3 stratum lucidum subregions. These subregions have been proposed to sustain two cognitive processes involved in memory functions: pattern separation and pattern completion. Pattern separation allows the encoding of similar or overlapping inputs in distinct neuronal representations, allowing formation of new memory without interference of a previous similar encountered event. Pattern completion is described as the ability to guide the recall of an entire memory using partial sensory cues. Recent studies suggest a critical role for the maturation of adult-born granule neurons of the DG in the balance that may exist between pattern completion and pattern separation. Although the mechanisms of both cognitive processes are still debated, the connectivity between DG and CA3 appears to be essential. I thereby tested the hypothesis that in absence of Vangl2 in the brain, these two processes would be affected. I generated several conditional mutant mice in order to excise vangl2 gene in specific areas of the hippocampus, and tested them in behavioral paradigms requiring pattern separation or pattern completion processes. My data support my hypothesis that Vangl2 in the DG is essential for a balance between pattern separation and pattern completion, through the regulation of the maturation of DG neurons
Modulation des interactions impliquant les domaines PDZ par une approche d'évolution dirigée by Charlotte Rimbault( )

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

Les interactions protéine-protéine (IPPs), complexes et dynamiques, sont le cœur des réseaux protéiques cellulaires. Au niveau des synapses excitatrices, la densité post-synaptique (PSD) est un exemple typique de réseau protéique dont la structure et la composition à l'échelle nanoscopique détermine la fonction cellulaire. Ainsi, la régulation dynamique de la composition de la PSD et des mouvements des récepteurs au glutamate dans ou hors de la PSD constitue la base des théories moléculaires actuelles sur l'apprentissage et la mémoire. Dans ce contexte, durant ma thèse, j'ai étudié une classe d'IPPs faisant intervenir les domaines PDZ. En effet, durant ces dernières années, de nombreuses études ont démontré l'implication de ces interactions impliquant les domaines PDZ de la famille de PSD95 dans le ciblage synaptique et l'ancrage des récepteurs au glutamate. Cependant, en partie dû au manque d'outils adaptés, les mécanismes moléculaires sous-jacents qui contrôlent de façon dynamique leur rétention à la synapse restent mal compris. Dans le but d'étudier ces interactions impliquant des domaines PDZ, j'ai développé plusieurs stratégies de sélection par phage display basées sur l'utilisation du dixième domaine de type III de la fibronectine humaine (10Fn3) dans le but de cibler les motifs d'interaction aux domaines PDZ des récepteurs (Stargazin pour les rAMPA et GluN2A pour les rNMDA) ou les domaines PDZ eux-mêmes. En utilisant une approche multidisciplinaire, mes objectifs principaux ont été de concevoir de petits anticorps synthétiques qui nous permettront de rompre ou de stabiliser spécifiquement ces complexes protéiques, ainsi que d'observer les interactions endogènes
Study on synaptic integration in granule cells of the dentate gyrus during behavioural discrimination in mice navigating in virtual reality by Ruy Gómez Ocádiz( )

1 edition published in 2021 in English and held by 1 WorldCat member library worldwide

Episodic memory formation and recall are complementary processes that put conflicting requirements on neuronal computations in the hippocampus. How this challenge is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments. We observe that the subthreshold membrane potential of silent granule cells shows robust selectivity across different virtual environments. This observation supports the notion that the sparse fraction of active granule cells results from competitive 'winner-takes-all' dynamics, in which the cells that receive enough excitatory input to fire action potentials recruit inhibition to silence the others. Furthermore, we find that granule cells consistently display a small transient depolarisation of their membrane potential upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on muscarinic acetylcholine receptors. A computational model suggests that the observed transient synaptic response to novel environments may lead to a bias in the granule cell population activity, which can in turn drive the downstream attractor networks to a new state, thereby favouring the switch from generalisation to discrimination when faced with novelty. Such a novelty-driven cholinergic switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones
Etude des mécanismes de régulation de la kinase neuronale PAK3 by Gaëlle Combeau( )

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

5 mutations responsables de retard mental ont été identifiées dans le gène p21-activated kinase 3 (pak3). Nous avons récemment identifiés dans pak3 deux exons alternatifs très conservés appelés b et c. Ainsi, en plus du variants PAK3a (dépourvu des inserts b ou c), le gène pak3 code pour 3 nouveaux variants d'épissage PAK3b, PAK3c et PAK3cb qui sont constitutivement actifs et insensibles aux GTPases. De plus, contrairement à PAK1 et PAK3a, leur domaine d'auto-inhibition est incapable d'inhiber un domaine kinase. Ainsi, le but de ce projet était de comprendre le mécanisme de régulation de la kinase PAK3. Un modèle de régulation a récemment été proposé dans lequel PAK1 forme des homodimères pouvant être dissociés par les GTPases, permettant ainsi l'activation de la kinase. En se basant sur ces observations j'ai cherché à identifier les dimères PAK3 et j'ai montré que les kinases PAK3a, b, c et cb forment préférentiellement des hétérodimères avec PAK1. J'ai démontré l'existence de ces dimères dans le cerveau et j'ai mis en évidence que ces hétérodimères permettent à chaque monomère de réguler l'activité kinase de son partenaire in vitro. Ce travail permet de proposer un modèle de régulation symétrique pour PAK3a qui forme des hétérodimères avec PAK1 et un nouveau modèle de régulation asymétrique pour les variants d'épissage, également basé sur leur hétérodimérisation avec PAK1. Mes résultats montrant une corégulation des kinases PAK neuronales suggèrent d'une part que leur activation puisse être synchronisée et d'autre part que dans certaines situations physiopathologiques (Cancer et maladies neurologiques) leur dérèglement puissent interférer
Implication fonctionnelle des récepteurs NMDA corticaux au cours des processus de consolidation systémique et d'oubli de la mémoire associative chez le rat by Benjamin Bessieres( )

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

Initially encoded in the hippocampus, new declarative memories are thought to become progressively dependent on a broadly distributed cortical network as they mature and consolidate over time. Although we have a good understanding of the mechanisms underlying the formation of new memories in the hippocampus, little is known about the cellular and molecular mechanisms by which recently acquired information is transformed into remote memories at the cortical level. The N--methyl--D--aspartate receptor (NMDAR) is widely known to be a key player in many aspects of long--term experience--dependent synaptic changes underlying associative memory processes. Based on their distinct biophysical properties, we postulated that the activity--dependent surface dynamics of the two predominant GluN2 subunits (GluN2A and GluN2B) of NMDARs present in the adult neocortex could provide a metaplastic control of synaptic plasticity supporting the progressive embedding and stabilization of long--lasting associative memories within cortical networks during memory consolidation. By combining, in adult rats, behavioral, biochemical, pharmacological and innovative strategies consisting in manipulating trafficking of NMDAR subunits at the cell membrane, our results identify a cortical switch in the synaptic GluN2--containing NMDAR composition which drives the progressive embedding and stabilization of long--lasting memories within cortical networks. We first established that cortical GluN2B--containing NMDARs and their specific interactions with the synaptic signaling CaMKII protein are preferentially recruited upon encoding of associative olfactory memories to enable neuronal allocation, the process via which a new memory trace is thought to be allocated to a given neuronal network. As these memories are progressively processed and embedded into cortical networks, we observed a learning--induced surface redistribution of cortical GluN2B--containing NMDARs outwards or inwards synapses which respectively drives the progressive stabilization and subsequent forgetting of remote memories over time. Finally, increasing the strength, upon encoding, of the initial memory leads to a faster increase of the cortical GluN2A/GluN2B synaptic ratio and accelerates the kinetics of hippocampal--cortical interactions, which translated into a faster stabilization of memories within cortical networks. Taken together, our results provide evidence that GluN2B--NMDAR surface trafficking controls the fate of remote memories (i.e. stabilization versus forgetting), shedding light on a novel mechanism used by the brain to organize recent and remote memories
 
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Nathalie Sans wetenschapper

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