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Contrôler la plasticité du cortex cérébral adulte à travers l'action non-autonome de l'homéoprotéine Otx2

Abstract : During postnatal development, extracellular Otx2 homeoprotein is preferentially internalized by parvalbumin (PV) interneurons of the visual cortex and regulates the critical period for ocular dominance plasticity. The specificity of Otx2 internalization is mediated by chondroitin sulfate type E (CS-E) which is a component of the extracellular matrix enriched in glycosaminoglycans that condenses around PV cells during the critical period. The continuous supply of Otx2 in adults is necessary to maintain a non-plastic state of the cerebral cortex. Thus, a reopening of plasticity is possible by disrupting Otx2 transfer. We developed a transgenic mouse line with inducible secretion of single chain antibodies directed against Otx2 to separate the autonomous and non-autonomous activity in order to study its role in the maturation of cortical PV cells. We found that this maturation involves direct regulation of Gadd45b/g genes by Otx2 and that Gadd45b may control plasticity by influencing the methylation state of DNA and thus the epigenetic status of PV cells. We have also developed easily synthesizable peptides that mimic CS-E and are able to interact in vivo with Otx2 to block its transfer. Tools for neutralizing extracellular Otx2 have significant therapeutic potential for critical period pathologies.
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  • HAL Id : tel-02479650, version 1

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Damien Testa. Contrôler la plasticité du cortex cérébral adulte à travers l'action non-autonome de l'homéoprotéine Otx2. Neurosciences [q-bio.NC]. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS234⟩. ⟨tel-02479650⟩

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