Homéostasie du métabolisme mitochondrial au cours du développement de l'hippocampe // Homeostasis of mitochondrial metabolism during hippocampal development

Sorbonne Université SIM (Sciences, Ingénierie, Médecine)
Plein temps Journée complète
Paris

Homéostasie du métabolisme mitochondrial au cours du développement de l'hippocampe // Homeostasis of mitochondrial metabolism during hippocampal development






Réf ABG-122136

ADUM-53755


Sujet de Thèse







03/04/2024



Contrat doctoral









Sorbonne Université SIM (Sciences, Ingénierie, Médecine)




Lieu de travail

Paris - France



Intitulé du sujet

Homéostasie du métabolisme mitochondrial au cours du développement de l'hippocampe // Homeostasis of mitochondrial metabolism during hippocampal development



Mots clés

Neurodéveloppement, migration neuronale, mitochondrie, hippocampe, pathologie neurologique, Cytosquelette

Neurodevelopment, neuronal migration, mitochondria, hippocampus, Neurological disorder, Cytoskeleton






Description du sujet



The hippocampus is an important brain structure for learning and memory. During the early stages of hippocampal development, radial glia progenitor cells divide in a neuroepithelium to generate immature hippocampal neurons (1). Pyramidal neurons are present in the CA1 to CA3 regions. The CA3 pyramidal cell layer is curved and its formation involves radial and tangential migration pathways. In association with cerebral cortical disorders, we have previously demonstrated the important role of certain intrinsic or microtubule-associated proteins during neuronal migration in the developing mouse brain (2, 3). The absence of tubulin alpha 1 (Tuba1a) and Doublecortin (Dcx) can severely impair normal migration and formation of the CA3 region, with a deleterious consequence on the excitability of pyramidal neurons (2, 4). In this new project, we will focus on the Dcx mutant mouse model that exhibits spontaneous epilepsy due to a malformation of the CA3 region of the hippocampus. While control mice show a single layer of CA3 pyramidal cells, Dcx mutant mice show a disorganized double layer (4). Because of disturbances in the dynamics of the neuronal migration process in Dcx mutants (3, 5, 6), it is generally assumed that this is related to problems in cytoskeleton dynamics. But it could also be due to a defect in ATP production and other metabolic abnormalities that directly impact migration efficiency. This has never been tested previously. During ontogeny, Dcx mutant CA3 neurons exhibit damaged mitochondria (7, 8). Already at birth, the mitochondria in mutant neurons are abnormal. Is it possible that these anomalies are causative of the migratory phenotype to form the CA3 region? To answer this question, and pursued by the PhD student, we plan first, to address if Dcx regulates mitochondrial transport during neuronal migration. Different state-of-art microscopes (among them the FAST-SIM microscope in collaboration with S. Bonneau and S. Kruglik at the Laboratoire Jean Perrin (LJP) – Sorbonne University) will be used in combination with mouse genetics, in order to perform live imaging studies on Dcx mutant neurons. Second, the functional integrity of Dcx mutant mitochondria will be tested by analyzing their specialized contacts with endoplasmic reticulum and their calcium uptake (by spinning disk microscopy). Third, a rescue attempt of the CA3 migratory phenotype will be tested using mitophagic drugs in Dcx mutant mice. While abnormal mitochondria and impaired mitochondrial homeostasis are often associated with neurodegenerative diseases (9), their involvement in the pathogenesis of neurodevelopmental disorders is poorly studied. Therefore, this new PhD project aims to decipher how regulation of mitochondrial metabolism is an important prerequisite for normal neuronal migration. It will also provide potential therapeutical strategies to overcome the deleterious consequences of mitochondrial defects in neurons during neurodevelopment







The hippocampus is an important brain structure for learning and memory. During the early stages of hippocampal development, radial glia progenitor cells divide in a neuroepithelium to generate immature hippocampal neurons (1). Pyramidal neurons are present in the CA1 to CA3 regions. The CA3 pyramidal cell layer is curved and its formation involves radial and tangential migration pathways. In association with cerebral cortical disorders, we have previously demonstrated the important role of certain intrinsic or microtubule-associated proteins during neuronal migration in the developing mouse brain (2, 3). The absence of tubulin alpha 1 (Tuba1a) and Doublecortin (Dcx) can severely impair normal migration and formation of the CA3 region, with a deleterious consequence on the excitability of pyramidal neurons (2, 4). In this new project, we will focus on the Dcx mutant mouse model that exhibits spontaneous epilepsy due to a malformation of the CA3 region of the hippocampus. While control mice show a single layer of CA3 pyramidal cells, Dcx mutant mice show a disorganized double layer (4). Because of disturbances in the dynamics of the neuronal migration process in Dcx mutants (3, 5, 6), it is generally assumed that this is related to problems in cytoskeleton dynamics. But it could also be due to a defect in ATP production and other metabolic abnormalities that directly impact migration efficiency. This has never been tested previously. During ontogeny, Dcx mutant CA3 neurons exhibit damaged mitochondria (7, 8). Already at birth, the mitochondria in mutant neurons are abnormal. Is it possible that these anomalies are causative of the migratory phenotype to form the CA3 region? To answer this question, and pursued by the PhD student, we plan first, to address if Dcx regulates mitochondrial transport during neuronal migration. Different state-of-art microscopes (among them the FAST-SIM microscope in collaboration with S. Bonneau and S. Kruglik at the Laboratoire Jean Perrin (LJP) – Sorbonne University) will be used in combination with mouse genetics, in order to perform live imaging studies on Dcx mutant neurons. Second, the functional integrity of Dcx mutant mitochondria will be tested by analyzing their specialized contacts with endoplasmic reticulum and their calcium uptake (by spinning disk microscopy). Third, a rescue attempt of the CA3 migratory phenotype will be tested using mitophagic drugs in Dcx mutant mice. While abnormal mitochondria and impaired mitochondrial homeostasis are often associated with neurodegenerative diseases (9), their involvement in the pathogenesis of neurodevelopmental disorders is poorly studied. Therefore, this new PhD project aims to decipher how regulation of mitochondrial metabolism is an important prerequisite for normal neuronal migration. It will also provide potential therapeutical strategies to overcome the deleterious consequences of mitochondrial defects in neurons during neurodevelopment







Début de la thèse : 01/10/2024

WEB : https://ifm-institute.org/equipe/francis-goutebroze/




Nature du financement



Contrat doctoral

Précisions sur le financement



Concours pour un contrat doctoral - SU



Présentation établissement et labo d'accueil



Sorbonne Université SIM (Sciences, Ingénierie, Médecine)




Etablissement délivrant le doctorat



Sorbonne Université SIM (Sciences, Ingénierie, Médecine)

Ecole doctorale



515 Complexité du vivant



Profil du candidat



• The student should have a Master 2 diploma in Sciences with a desired training in neurobiology, developmental and / or cellular biology. In particular, he/she should have an in-depth knowledge and interest in molecular and cellular biology, potentially applied to neuroscience. If possible, knowledge of mitochondrial metabolism would be an advantage. • Since the experimental work will mainly be performed with mouse mutant models, knowledge in animal biology and animal experimentation (rodents) would be a benefit although not a prerequisite. • Competences in state-of-the-art imaging would be useful to help advance the experiments, although the conditions of imaging are now defined. • These experiments require precision, rigor in the application of methods and manual dexterity especially for mouse brain dissections for histology and primary neuronal cell cultures. The student should be able to plan and coordinate the different phases of a research protocol and to perform cellular analysis. • The team and the institute are composed of international students and researchers and the student should be able to interact with other members of the Institute at all levels. A good knowledge of English is required

• The student should have a Master 2 diploma in Sciences with a desired training in neurobiology, developmental and / or cellular biology. In particular, he/she should have an in-depth knowledge and interest in molecular and cellular biology, potentially applied to neuroscience. If possible, knowledge of mitochondrial metabolism would be an advantage. • Since the experimental work will mainly be performed with mouse mutant models, knowledge in animal biology and animal experimentation (rodents) would be a benefit although not a prerequisite. • Competences in state-of-the-art imaging would be useful to help advance the experiments, although the conditions of imaging are now defined. • These experiments require precision, rigor in the application of methods and manual dexterity especially for mouse brain dissections for histology and primary neuronal cell cultures. The student should be able to plan and coordinate the different phases of a research protocol and to perform cellular analysis. • The team and the institute are composed of international students and researchers and the student should be able to interact with other members of the Institute at all levels. A good knowledge of English is required.


Date limite de candidature

07/06/2024






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