ED Mathématiques et Informatique
On duality theorems for the condensed cohomology of the Weil group of a p-adic field
by Marco ARTUSA (IMB - Institut de Mathématiques de Bordeaux)
The defense will take place at 14h00 - Salle de Conférences Institut de Mathématiques de Bordeaux, Université de Bordeaux 351, cours de la Libération Bâtiment A33 33400 Talence
in front of the jury composed of
- Baptiste MORIN - Chargé de recherche - Institut de Mathématiques de Bordeaux - Université de Bordeaux - Directeur de these
- Tamás SZAMUELY - Professor - Università degli studi di Pisa - Rapporteur
- Clark BARWICK - Professor - School of Mathematics - University of Edinburgh - Rapporteur
- Olivier BRINON - Professeur des universités - Institut de Mathématiques de Bordeaux - Université de Bordeaux - Examinateur
- Cédric PéPIN - Maître de conférences - Département de Mathématiques - Institut Galilée - Université Sorbonne Paris Nord - Examinateur
- Wiesława NIZIOL - Directrice de recherche - Sorbonne Université - Examinateur
- Arthur-César LE BRAS - Chargé de recherche - Institut de Recherche Mathématique Avancée - Université de Strasbourg - Examinateur
The goal of this thesis is twofold. First, we build a topological cohomology theory for the Weil group of p-adic fields. Secondly, we use this theory to prove duality theorems for such fields, which manifest as Pontryagin duality between locally compact abelian groups. These results improve existing duality theorems and give them a topological flavour. Condensed Mathematics allow us to reach these objectives, providing a framework where it is possible to do algebra with topological objects. We define and study a cohomology theory for condensed groups and pro-condensed groups, and we apply it to the Weil group of a p-adic field, considered as a pro-condensed group. The resulting cohomology groups are proved to be locally compact abelian groups of finite ranks in some special cases. This allows us to enlarge the local Tate duality to a more general category of non-necessarily discrete coefficients, where it takes the form of a Pontryagin duality between locally compact abelian groups. In the last part of the thesis, we use the same framework to recover a Weil-version of the Tate duality with coefficients in abelian varieties and more generally in 1-motives, expressing those dualities as perfect pairings between condensed abelian groups. To do this, we associate to every algebraic group, resp. 1-motive, a condensed abelian group, resp. a complex of condensed abelian groups, with an action of the (pro-condensed) Weil group. We call this association the condensed Weil-étale realisation. Under the assumption of the existence of certain cup-product pairings between cohomology groups, we prove two duality theorems for the condensed cohomology of the Weil group: the first one is a condensed-Weil version of the Tate duality with coefficients in abelian varieties and improves the correspondent result of Karpuk. The second one is a duality theorem with coefficients in 1-motives and improves a result of Harari-Szamuely.
ED Sciences de la Vie et de la Santé
Metabolic role of the ATP-synthase Inhibitory Factor 1 under physiological and pathological conditions
by Orane LEROULEY (Institut de Biochimie et Génétique Cellulaires)
The defense will take place at 14h00 - Salle de conférence Institut de Biochimie et Génétique Cellulaires, UMR 5095, 1 rue Camille Saint Saens 33077 Bordeaux
in front of the jury composed of
- Amandine MARECHAL - Associate Professor - University College London - Rapporteur
- Francis HARAUX - Retraité Directeur de recherche - Institut de Biologie Intégrative de la Cellule (I2BC) - UMR9198 - Examinateur
- Giovanni BENARD - Directeur de recherche - Maladies rares : Génétique et métabolisme - Examinateur
- Geneviève DUJARDIN - Directrice de recherche émérite - Institut de Biologie Intégrative de la Cellule (I2BC) - UMR9198 - Rapporteur
F1Fo ATP synthase is a multi-protein machinery that converts the energy of an electrochemical gradient into chemical energy in the form of ATP. This protein complex is anchored in the mitochondrial inner membrane by its Fo sector, which is itself physically associated with an intra-mitochondrial F1 catalytic sector. This mitochondrial enzyme plays a key role in energy metabolism. Yeast and mammalian ATP synthase, are reversible enzymes and this hydrolytic activity is regulated by an endogenous inhibitor: IF1. In yeast, another inhibitor peptide, STF1, has been identified. Inhibition of ATP synthase by IF1/STF1 is pH-dependent, so these inhibitors are inactive under physiological conditions where mitochondrial are polarised, but IF1/STF1 are particularly active under pathological conditions of depolarisation. Intriguingly, the metabolic and pathophysiological importance of IF1/STF1 has been challenged by yeast and mouse models showing that the loss of this inhibitor has almost no detectable impact on the metabolism or physiology of these organisms. My thesis work investigated the mechanisms of action of these inhibitors on ATP synthase, associated or not with energy stresses affecting the mitochondrial polarization state. My work has highlighted a new mechanism of action for IF1 by demonstrating that it controls the stability and maintenance of the ATP synthase sub-assembly, the free F1 (soluble F1 sector not associated with the F0 sector). The presence of this catalytic sector, disconnected from the proton motor force, represents a serious energetic threat. The potential energetic toxicity of free F1 is annihilated through two mechanisms: (i) the direct canonical inhibition of IF1/STF1, or (ii) the instability and physical disappearance of free F1 in absence of IF1/STF1. My thesis work also defined that the action of IF1/STF1 was particularly crucial under mitochondrial depolarization stress conditions in glyco-oxidative metabolism observed in glycerol medium. Under these conditions, the phosphate potential is co-dependent on ATP synthase and substrate phosphorylation of glycolytic kinases, and cell proliferation under depolarisation stress relies on IF1/STF1 activity.
Synaptic plasticity in a memory circuit: physiological and pathophysiological role of the amyloid precursor protein
by Ana MOREIRA DE SÁ (Institut Interdisciplinaire de Neurosciences)
The defense will take place at 14h00 - Amphi Centre Broca Nouvelle-Aquitaine IINS - UMR 5297 - Centre Broca Nouvelle-Aquitaine 146 rue Léo Saignat CS 61292 Case 130 33076 Bordeaux Cedex (FRANCE)
in front of the jury composed of
- Nathalie SANS - Directrice de recherche - Université de Bordeaux - Examinateur
- Nelson REBOLA - Directeur de recherche - Sorbonne Université - Rapporteur
- Joris DE WIT - Professeur agrégé - KU Leuven - Rapporteur
- Marie-Claude POTIER - Directrice de recherche - Sorbonne Université - Examinateur
- Noa LIPSTEIN - Chargée de recherche - Forschungsverbund Berlin e.V. (FVB) - Examinateur
- Christophe MULLE - Directeur de recherche - Université de Bordeaux - Directeur de these
The full-length amyloid precursor protein (APP), a key player in Alzheimer's disease (AD), is ubiquitously expressed throughout the brain. APP is abundantly expressed in presynaptic compartments where it interacts with proteins of the presynaptic release machinery. However, the physiological functions of APP at synapses remain in great part elusive. In this work, we study the physiological role of APP in short-term synaptic plasticity and information transfer within the hippocampus circuitry. Our work focuses on the CA3 region of the hippocampus and on mossy fiber (MF) synapses between the axons of the dentate gyrus (DG) and CA3 pyramidal cells (CA3 PCs). We deleted APP and the related protein APLP2 in DG granular cells (DG-GCs) using a viral gene transfer strategy in APP/APLP2 double floxed mice. By combining optogenetics and ex vivo electrophysiology, we found that the selective deletion of APP in DG-GCs strongly impairs presynaptic short term plasticity at MF-CA3 PC synapses, expressed as a high level of synaptic facilitation in response to repeated presynaptic stimulation, without altering nor basal synaptic properties nor intrinsic excitability of DG-GCs. Additionally, the lack of APP altered the time course of post-tetanic potentiation, a form of presynaptic plasticity lasting several minutes following a high frequency train of stimulation. We then investigated the molecular mechanisms by which APP controls presynaptic short-term plasticity by isolating GFP-labelled MF-CA3 synaptosomes, and by performing a comparative proteomic screening to identify presynaptic proteins dysregulated in the absence of APP. We identified prospectively interesting targets that are dysregulated, including ZnT3, complexins I and II, and CSPalpha. We discuss the potential causative role of these proteins in the observed functional deficits, as well as the possible mechanisms by which APP controls presynaptic plasticity. Concurrently, we virally deleted APP and APLP2 in postsynaptic CA3 PCs and performed ex vivo electrophysiology. We discovered that the lack of APP in CA3 pyramidal cells leads to a selective downregulation of MF-CA3 EPSCs mediated by kainate receptors (KARs), but not by AMPA or NMDA receptors. This was also observed in the APP/PS1 mouse model of AD and in conditional presenilin KO mice. We report that the GluK2 subunit of KARs interacts with APP and its biologically active fragments, and this interaction is likely responsible for regulating synaptic KARs levels. We interpret these results by a previously unknown transsynaptic role for APP. Altogether, our data supports a pivotal role of APP in synaptic transmission and plasticity mechanisms at the MF-CA3 synapse. We propose that shedding light on the physiological contribution of full-length APP in the activity of hippocampal circuits will enhance our understanding of how disruption of APP functions contributes to the pathophysiology of AD.