Discussion générale

Les travaux présentés dans le cadre de cette thèse mettent en évidence un nouveau rôle de Tau dans la physiologie rétinienne et dans les mécanismes de neuroplasticité dans le système visuel chez la souris adulte. Contrairement à l’hippocampe, le système visuel ne semble pas être affecté par la surexpression de Tau humaine dans un modèle de tauopathie soulevant ainsi la question d’une possible toxicité différentielle de Tau au sein même du système nerveux central. La modulation de l’expression des isoformes de Tau lors de la réactivation de la plasticité fonctionnelle chez l’adulte est très intéressante et devrait être également étudiée au cours de la période critique. Bien que le modèle de souris Tau KO présente ses limites, il a permis de démontrer l’importance de Tau dans la plasticité de la dominance oculaire chez l’adulte. Par ailleurs, à la vue des résultats portant sur l’influence de Tau dans la régénération axonale, la modulation d’isoformes spécifiques de Tau semble prometteuse. Pris ensemble, ces résultats viennent donc enrichir les connaissances quant au rôle de Tau dans la physiologie rétinienne et l’établissement de mécanismes de plasticité dans le système visuel chez la souris adulte. Ces résultats soulèvent également de nombreuses nouvelles questions concernant l’implication de Tau dans la neuroplasticité visuelle.

CONCLUSION GÉNÉRALE

La vision est inséparable de notre conception du monde. Cependant, cette perception de notre monde résulte de processus physiologiques et adaptatifs complexes. Ces processus adaptatifs font référence aux mécanismes de plasticité et à leur capacité à remodeler structurellement et fonctionnellement les circuits neuronaux. Fondamentale, la plasticité neuronale permet de s’adapter à son environnement. Les processus neurodéveloppementaux et adaptatifs consécutifs à une lésion dépendent en grande partie de mécanismes de plasticité, retrouvés dans l’ensemble du système nerveux central. De nombreux acteurs de la physiologie et de la plasticité neuro-visuelle ont été étudiés, souvent avec un objectif thérapeutique. Associée aux processus neurodégénératifs sous-jacents à de nombreuses neuropathologies, Tau, une protéine associée aux microtubules, n’a jamais été étudiée dans la physiologie rétinienne et la plasticité visuelle.

Dans ce contexte, les travaux présentés dans cette thèse visaient à étudier le rôle de Tau dans la physiologie rétinienne au cours du vieillissement et dans deux mécanismes de neuro- plasticité soit l’expérience dépendante de l’expérience visuelle et la régénération axonale chez la souris adulte.

Nos résultats démontrent pour la première fois que la protéine Tau n’influence pas la physiologie rétinienne au cours du vieillissement. Par ailleurs, en utilisant un modèle modéré de tauopathie, nous avons mis en évidence une toxicité différentielle de Tau entre le système visuel et l’hippocampe. En utilisant le modèle de privation monoculaire chez la souris adulte, nos résultats ont mis en avant une nouvelle fonction de Tau en tant que modulateur dans les mécanismes adaptatifs de plasticité oculaire opérant dans le cerveau adulte soumis à des changements d'expérience sensorielle. Enfin, en utilisant le modèle de lésion du nerf optique, nos résultats ont montré que Tau n’influence pas la survie neuronale et la régénération axonale même lorsque la croissance axonale est stimulée.

En conclusion, au-delà de nos résultats obtenus dans le système visuel, nos travaux mettent en évidence l’importance de continuer à disséquer l’implication de Tau dans la physiologie et la plasticité du système nerveux central adulte. En ce sens, plusieurs stratégies préventives ou thérapeutiques ont été ou sont actuellement testées et impliquent une modulation de l’expression de Tau.

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