Influence de Tau sur la physiologie rétinienne et la neuroplasticité visuelle chez la souris adulte
|Abstract:||The visual system allows us to analyze and interpret the world around us. The integration of visual stimuli results from complex physiological and adaptive processes. These adaptive processes refer to the mechanisms of plasticity and their ability to structurally and functionally reshape neural circuits. Basically, neuronal plasticity allows to adapt to the environment. The neurodevelopmental and adaptive processes consecutive to a lesion are largely dependent on mechanisms of plasticity found throughout the central nervous system. Many factors in physiology and neuro-visual plasticity have been studied, often with a therapeutic objective. Associated with the neurodegenerative processes underlying many neuropathologies, Tau, a microtubule-associated protein playing a role in synaptic remodeling but also in the dynamics of the cytoskeleton, has never been studied in retinal physiology and visual plasticity. Our hypothesis is that in adult mice, Tau influences retinal physiology and the mechanisms of visual neuroplasticity. Our first objective was to study the influence of the Tau protein in retinal physiology during aging. We compared mice expressing human Tau protein in a model of moderate tauopathy (hTau) to mice deficient in Tau protein (Tau KO). The influence of the Tau protein in the retina is most often studied from a pathological point of view in severe tauopathy models associated with an overexpression of mutated Tau or a pathological increase in its phosphorylation. Our choice to study hTau mice was based on the fact that these mice express the unmutated human Tau protein and therefore represent a model closer to what is found in humans. This study demonstrated that the Tau protein expression does not influence retinal physiology during aging. Also, this study suggested differential neuronal toxicity of Tau between the retina and the brain. Our second objective was to study the influence of Tau in visual experience-dependent plasticity in adult mice using the monocular deprivation model. Tau protein has been reported to be involved in long-term potentiation mechanisms. This study demonstrated in wild mice (WT) that the expression of Tau was modulated during development but also during the induction of visual plasticity in response to monocular deprivation in the visual cortex. Thanks to the study of the optokinetic reflex, using Tau KO mice and WT controls, our results showed that Tau limits visual plasticity in adults. Analysis of visual cortices revealed a higher level of expression of proteins associated with plasticity in Tau KO mice. These findings highlighted that Tau protein is an important factor in visual plasticity of the adult mice. Our third objective was to study the role of Tau in neuronal survival and axonal regeneration in a model of optic nerve damage in adult mice. Neuronal survival was quantified on whole flat-mount retinae and regeneration by counting stained regenerated axons using an anterograde tracer injected into the vitreous humor. Using Tau KO and WT mice, our analyzes demonstrated that the Tau protein does not influence survival or axonal regeneration significantly, even when axonal regrowth was improved by the sustained release of CNTF (ciliary neurotrophic factor), a neurotrophic factor. These data demonstrated that Tau does not influence retinal survival and neuronal regeneration in adults. All of our results therefore suggest that: 1 / Tau does not influence retinal physiology during aging and in a mild model of tauopathy, 2 / Tau limitates plasticity dependent on visual experience and 3 / Tau does not influence retinal survival and axonal regeneration mechanisms of the optic nerve. Overall, this work highlights Tau's involvement in physiological and neuronal plasticity mechanisms in the visual system. This new role of Tau could ultimately lead to the development of new therapeutic strategies in the visual system but also more generally in the central nervous system during alterations in neuronal plasticity.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||8 February 2021|
|Collection:||Thèses et mémoires|
All documents in CorpusUL are protected by Copyright Act of Canada.