A modularity based spectral method for simultaneous community and anti-community detection

In a graph or complex network, communities and anti-communities are node sets whose modularity attains extremely large values, positive and negative, respectively. We consider the simultaneous detection of communities and anti-communities, by looking at spectral methods based on various matrix-based definitions of the modularity of a vertex set. Invariant subspaces associated to extreme eigenvalues of these matrices provide indications on the presence of both kinds of modular structure in the network. The localization of the relevant invariant subspaces can be estimated by looking at particular matrix angles based on Frobenius inner products

Etude de la dynamique de tau dans le compartiment synaptique dans un contexte physiologique et pathologique exemple de la maladie d'Alzheimer

La maladie d'Alzheimer est une pathologie neurodégénérative caractérisée par une perte progressive des fonctions cognitives. Cette perte des fonctions cognitives est directement liée à une atteinte neuronale et plus particulièrement synaptique. Deux caractéristiques histopathologiques en lien avec des dérégulations protéiques sont retrouvées chez les patients atteints de la MA : les plaques séniles extracellulaires composées de peptides b-amyloïdes (Ab) fibrillaires et la dégénérescence neurofibrillaire constituée d'agrégats intracellulaires de protéines tau hyper et anormalement phosphorylées. Les formes agrégées de ces protéines ont longtemps été considérées comme neurotoxiques, cependant, il est maintenant avéré que les formes solubles de ces protéines dérégulées étaient à l'origine de la pathologie. Les synapses excitatrices situées au niveau des épines dendritiques sont les cibles du peptide Ab sous forme soluble et oligomèrique (Abo). Ce dernier en altère la fonction et induit leurs pertes. Récemment, il a été montré que cette action synaptotoxique de l'Abo est dépendante de la protéine tau. De plus, dans un autre modèle de tauopathie, la démence fronto-temporale avec syndrome parkinsonien liée au chromosome 17 (FTDP-17), la synaptotoxicité de tau s'est révélée dépendante de son état de phosphorylation. Ainsi, il émerge le concept de tau synaptique dans un contexte pathologique. Cependant, des études plus récentes ont montré que, en condition physiologique, une petite portion de tau se retrouve au niveau de la synapse. Au regard de ces nouvelles données, il est possible que tau, en plus d'être une protéine axonale, nucléaire et membranaire, soit aussi synaptique. Dans ce contexte, les travaux présentés dans cette thèse visent à étudier l'implication de la protéine tau dans la fonction synaptique et les perturbations induites par la présence d'Abo. Ces travaux ont été effectués sur un modèle cellulaire de cultures primaires de neurones corticaux et sur tranche d'hippocampe de souris par des méthodes biochimiques et d'analyse dynamique en microscopie confocale sur cellules vivantes. Afin d'étudier l'impact d'une activation synaptique sur un système de culture neuronal, l'utilisation combinée de la bicuculline, antagoniste des récepteurs gabaergique GABAa et de 4-amino pyridine, bloqueur de canaux potassique, permet d'établir une potentialisation à long terme sur les synapses. Grâce à un protocole d'extraction permettant d'isoler le compartiment post-synaptique (fraction contenant la densité post synaptique dont le marqueur protéique PSD-95), nous avons montré que l'activation synaptique enrichit la fraction PSD en protéine tau suggérant son implication dans les phénomènes de plasticité synaptique. L'étude du cytosquelette d'actine prépondérant au niveau synaptique a révélé que l'actine filamenteuse est un partenaire de tau. Dans un contexte pathologique, l'incubation d'Abo induit le recrutement de tau à la synapse et perturbe l'organisation du cytosquelette d'actine. Ce changement structurel du cytosquelette d'actine pourrait être à l'origine des perturbations de la plasticité et du maintien synaptique induit par Abo. En conclusion, l'ensemble des résultats de cette thèse suggère que tau exerce une fonction physiologique au sein de la synapse impliquant une interaction avec le cytosquelette d'actine et qu'en conditions pathologiques (induites par Abo), on observe une altération fonctionnelle du rôle de tau à la synapse qui pourrait participer aux perturbations cognitives caractéristiques de la MA.Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of cognitive functions. This loss of cognitive functions is directly related to neuronal impairment, and more specifically, synaptic dysfunction. Two histopathological features found in AD patients' brains are related to protein deregulation: extracellular neuritic plaques composed of fibrillar b-amyloid peptide (Ab) and intracellular aggregates composed of hyper-phosphorylated tau, named neurofibrillary tangles. Aggregated forms of these peptides have been considered neurotoxic, however, it is now recognized that soluble forms of these deregulated proteins are causal to the pathology. Soluble, oligomeric forms of Ab peptide (Abo) target excitatory synapses where they diminish synaptic function and cause loss of dendritic spines. Recently, it has been shown that the Abo synaptotoxicity is tau-dependent. Another tauopathy, fronto-temporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), exhibits synaptotoxicity, which has proved to be dependent on the phosphorylation state of tau. Thus, emerged the concept of synaptic tau in a pathological context. Recent studies have shown that a small quantity of tau is present in synapses under physiological conditions. These new data suggest that tau is a synaptic protein, in addition to being axonal, nuclear and membrane-associated. In this context, the work presented in this thesis characterizes the involvement of tau in synaptic function and its Abo-induced disturbances. This work was conducted using primary cortical neurons cultured from mice and hippocampus slices and employed biochemical methods and confocal live-cell imaging. To study the impact of a synaptic activation on synaptic tau, we combined bicuculline, an antagonist of GABAa receptors and 4-amino-pyridine, potassium channel blocker, to establish long-term synaptic potentiation. By isolating the post-synaptic compartment (i.e. the fraction containing the post synaptic density and its marker PSD-95), we have shown that synaptic activation induced an enrichment of tau in PSD. This suggests its involvement in synaptic plasticity. The study of the actin cytoskeleton, which is specifically enriched in dendritic spines, revealed that filamentous actin is a molecular partner of tau, which may provide a means of recruiting tau to the synapse. Turning our attention to a pathological context, exposure to Abo induced tau recruitment to the synapse and disrupts the actin cytoskeleton organization without exogenous synaptic stimulation. This structural modification of the actin cytoskeleton could underlie the disturbance of plasticity and synaptic maintenance induced by Abo. In conclusion, this thesis provides evidence that tau performs a physiological synaptic function that involves an interaction with the actin cytoskeleton. Further, the synaptic function of tau is altered in pathological conditions (i.e. exposure to Abo), and may contribute to the cognitive disturbances in AD.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

A quoi reconnaît-on une ville internationale ? Tentative de réponse par consultation d'experts. (Méthode Delphi)

En jetant un regard sur les écrits qui concernent le thème de la ville international, on aperçoit trois séries d'interrogation qui se complètent et suggèrent une progression très classique, depuis une compréhension élémentaire des choses jusqu'à des prescriptions de politiques économiques : le pourquoi, les enjeux et le comment. Pourquoi ce thème a-t-il émergé aussi nettement à la fin des années 80 ? De nombreuses explications ont pu être avancées, qui très vraisemblablement se conjuguent : la crise des Etats, débordés dans leurs fonctions centralisées par la complexité croissante des réalités du terrain ; l'internationalisation de la production et des échanges qui s'appuie sur des réseaux dont les fonctions nodales se multiplient et se diversifient ; la mondialisation des relations financières, ou, comme le disent les anglo-saxons, leur globalisation ; et peut-être surtout, au-delà des services financiers, l'explosion des " invisibles ", qui représentent aujourd'hui plus du tiers des échanges marchands internationaux. Les enjeux de l'accès au statut de ville internationale sont encore mal connus et pourtant déjà enviés. C'est que sont généralement concernés des activités à forte valeur ajoutée, des services auxiliaires du " haut de gamme " et, plus généralement, une image, bien faite pour que soit auto-entretenu le processus de développement des activités internationales. Le comment devient alors une question bien naturelle, qui consiste à repérer les voies et moyens d'accès à cette situation enviée ou à distinguer, du moins, les initiatives qui pourraient en favoriser l'approche.Delphi (méthode) ; ville internationale ; Enquête d'opinion

Density of GABAB receptors is reduced in granule cells of the hippocampus in a mouse model of Alzheimer's disease

Metabotropic γ-aminobutyric acid (GABAB) receptors contribute to the control of network activity and information processing in hippocampal circuits by regulating neuronal excitability and synaptic transmission. The dysfunction in the dentate gyrus (DG) has been implicated in Alzheimer´s disease (AD). Given the involvement of GABAB receptors in AD, to determine their subcellular localisation and possible alteration in granule cells of the DG in a mouse model of AD at 12 months of age, we used high-resolution immunoelectron microscopic analysis. Immunohistochemistry at the light microscopic level showed that the regional and cellular expression pattern of GABAB1 was similar in an AD model mouse expressing mutated human amyloid precursor protein and presenilin1 (APP/PS1) and in age-matched wild type mice. High-resolution immunoelectron microscopy revealed a distance-dependent gradient of immunolabelling for GABAB receptors, increasing from proximal to distal dendrites in both wild type and APP/PS1 mice. However, the overall density of GABAB receptors at the neuronal surface of these postsynaptic compartments of granule cells was significantly reduced in APP/PS1 mice. Parallel to this reduction in surface receptors, we found a significant increase in GABAB1 at cytoplasmic sites. GABAB receptors were also detected at presynaptic sites in the molecular layer of the DG. We also found a decrease in plasma membrane GABAB receptors in axon terminals contacting dendritic spines of granule cells, which was more pronounced in the outer than in the inner molecular layer. Altogether, our data showing post- and presynaptic reduction in surface GABAB receptors in the DG suggest the alteration of the GABAB-mediated modulation of excitability and synaptic transmission in granule cells, which may contribute to the cognitive dysfunctions in the APP/PS1 model of A

Reduction in the neuronal surface of post and presynaptic GABA>B< receptors in the hippocampus in a mouse model of Alzheimer's disease

The hippocampus plays key roles in learning and memory and is a main target of Alzheimer's disease (AD), which causes progressive memory impairments. Despite numerous investigations about the processes required for the normal hippocampal functions, the neurotransmitter receptors involved in the synaptic deficits by which AD disables the hippocampus are not yet characterized. By combining histoblots, western blots, immunohistochemistry and high‐resolution immunoelectron microscopic methods for GABAB receptors, this study provides a quantitative description of the expression and the subcellular localization of GABAB1 in the hippocampus in a mouse model of AD at 1, 6 and 12 months of age. Western blots and histoblots showed that the total amount of protein and the laminar expression pattern of GABAB1 were similar in APP/PS1 mice and in age‐matched wild‐type mice. In contrast, immunoelectron microscopic techniques showed that the subcellular localization of GABAB1 subunit did not change significantly in APP/PS1 mice at 1 month of age, was significantly reduced in the stratum lacunosum‐moleculare of CA1 pyramidal cells at 6 months of age and significantly reduced at the membrane surface of CA1 pyramidal cells at 12 months of age. This reduction of plasma membrane GABAB1 was paralleled by a significant increase of the subunit at the intracellular sites. We further observed a decrease of membrane‐targeted GABAB receptors in axon terminals contacting CA1 pyramidal cells. Our data demonstrate compartment‐ and age‐dependent reduction of plasma membrane‐targeted GABAB receptors in the CA1 region of the hippocampus, suggesting that this decrease might be enough to alter the GABAB‐mediated synaptic transmission taking place in AD

Responses of reptile populations to the eradication of the Roof Rat (Rattus rattus) on Bagaud Island (Port-Cros National Park, Var, France)

En 2011, une opération d’éradications simultanées de 2 taxa exotiques envahissants, le Rat noir (Rattus rattus) et les Griffes de sorcière (Carpobrotus spp.) a été entreprise sur l’île de Bagaud, réserve intégrale située au sein du Parc national de Port Cros, dans le sud-est de la France. Un contrôle réalisé en 2014 a permis de conclure au succès de l’éradication de R. rattus. L’éradication de Carpobrotus spp., quant à elle, est encore en cours. Afin de connaître les effets de l’opération d’éradication de R. rattus sur les populations de reptiles de l’île (la Couleuvre de Montpellier Malpolon monspessulanus, le Phyllodactyle d’Europe Euleptes europaea, le Lézard des murailles Podarcis muralis), un suivi pré-éradication a été réalisé en 2010 et 2011, et reconduit post-éradication, en 2013 et 2014. L’échantillonnage pratiqué a été semi-quantitatif selon trois méthodes : (1) trois transects de 80 m de long sur 2 m de large ; (2) deux quadrats de 1225 m² ; (3) cinq microsites rocheux à E. europaea. Très peu d’individus de M. monspessulanus ont été observés. Des résultats significatifs ont été observés seulement pour E. europaea : après éradication, le nombre de juvéniles observés a augmenté et l’ensemble des individus observés, quelle que soit leur classe d’âge, l’ont été plus hors que dans des abris. Ces résultats peuvent s’expliquer par la perte du comportement d’évitement que E. europaea avait en présence de R. rattus et par une pression de prédation plus faible, les deux espèces étant nocturnes. Le temps écoulé depuis l’éradication de R. rattus est assez court et certaines espèces n’ont pas encore nécessairement réagi de façon visible sur le plan démographique. Les suivis complémentaires dans les années à venir apporteront d’autres éléments d’information.An eradication of two invasive taxa, the Roof Rat (Rattus rattus) and Ice plants (Carpobrotus spp.), was undertaken in 2011 and 2012 on the protected nature reserve of Bagaud island, located in Port-Cros national Park (south-eastern France). R. rattus eradication was successful while Carpobrotus spp. eradication is still in progress. To assess the effects of R. rattus eradication on island reptile populations (Montpellier Snake Malpolon monspessulanus, European Leaf-toed Gecko Euleptes europaea, Common Wall Lizard Podarcis muralis), a pre-eradication monitoring was conducted in 2010 and 2011, and a post-eradication monitoring in 2013 and 2014. Census was performed with three semi-quantitative methods: (1) three transects of 80 m long and 2 m wide ; (2) two quadrats 1225 m²; (3) five rocky microsites, habitats for E. europaea. Very few individuals of M. monspessulanus were observed. Significant results were obtained only for E. europaea: after eradication, the number of observed juveniles increased and all observed individuals, independently of their age groups, were more outside shelters than inside. These results can be explained by the loss of avoidance behaviour that E. europaea displayed when in presence of R. rattus, and by lower predation pressure, given that both species are nocturnal. The elapsed time since eradication of R. rattus is quite short and some species have not necessarily visibly responded demographically. Additional monitoring in the coming years will provide further insights

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans

Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease

: Microtubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions which go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase. Here we show that tubulin tyrosine ligase hemizygous mice exhibit decreased tyrosinated microtubules, reduced dendritic spine density, and both synaptic plasticity and memory deficits. We further report decreased tubulin tyrosine ligase expression in sporadic and familial Alzheimer's disease, and reduced microtubule dynamics in human neurons harboring the familial APP-V717I mutation. Finally, we show that synapses visited by dynamic microtubules are more resistant to oligomeric amyloid β peptide toxicity and that expression of tubulin tyrosine ligase, by restoring microtubule entry into spines, suppresses the loss of synapses induced by amyloid β peptide. Together, our results demonstrate that a balanced tyrosination/detyrosination tubulin cycle is necessary for the maintenance of synaptic plasticity, is protective against amyloid β peptide-induced synaptic damage, and that this balance is lost in Alzheimer's disease, providing evidence that defective tubulin retyrosination may contribute to circuit dysfunction during neurodegeneration in Alzheimer's disease

Loss of function of RIMS2 causes a syndromic congenital cone-rod synaptic disease with neurodevelopmental and pancreatic involvement

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD