Le récepteur 5-HT6 et la dynamique de son réceptosome : rôle dans la différenciation neuronale et potentiel thérapeutique pour le traitement des troubles de spectre de l'autisme

Abstract : The serotonin 5-HT6 receptor, one of the most recently cloned serotonin receptors, is a promising target for the treatment of cognitive deficits of both schizophrenia and Alzheimer’s disease. 5-HT6 receptor blockade by antagonists exerts pro-cognitive effects in a wide range of models of cognitive impairment in rodents and some of them are in phase III of clinical trials in schizophrenia and Alzheimer’s disease. The 5-HT6 receptor is exclusively expressed in the central nervous system, where it is detected at early phases of brain development. Studies have shown that 5-HT6 receptors have a key influence upon migration of both pyramidal neurons and interneurons of the cerebral cortex (Riccio et al. Mol Psychiatry 14(3):280-90, 2009 ; Transl Psychiatry 11;1:e47, 2011; Jacobshagen et al. Development, in revision). Using a proteomic strategy, our team recently identified a network of proteins interacting with the carboxy-terminal domain of the receptor. These include Cyclin-dependent kinase (Cdk)5 and some of its substrates, which are known to control neuro-developmental processes such as neuronal migration, neurite growth and dendritic spine morphogenesis. We have also demonstrated that the expression of the 5-HT6 receptor elicits neurite growth in an agonist-independent manner through a mechanism involving receptor phosphorylation at a serine residue by associated Cdk5 and engagement of the Rho GTPase Cdc42 (Duhr et al. Nature Chem. Biol., in revision). These studies show for the first time a constitutive activation of a G protein-coupled receptor mediated by its phosphorylation by an associated protein kinase. Preliminary experiments performed by the team also revealed that 5-HT6 receptors activation decreases the number of dendritic spines and modify spine morphology in hippocampal neurons in primary culture. This thesis project aims at characterizing the signalling mechanisms underlying the control of dendritic spine morphogenesis by the 5-HT6 receptors. Particular attention will be paid to Cdk5 and its substrate WAVE1, a protein known to induce neurite growth via the activation of the Arp2/3 complex (also identified in the 5-HT6 receptor interactome), which promotes actin polymerization. As phosphorylation of WAVE1 by Cdk5 inhibits its activity, we hypothesize that Cdk5-elicited phosphorylation of WAVE1 in the receptor-associated complex might underlies its control of spine morphogenesis. This project will combine in vitro studies performed on primary cultured hippocampal neurons and in vivo studies using transgenic mice expressing GFP tagged 5-HT6 receptors (this mouse line is currently being generated). We will also take advantage of this model to perform a novel interactomics screen to identify in an authentic tissue context novel receptor partners potentially involved in dendritic spine formation. This project should reveal novel cellular targets for the alleviation of the currently untreated and strongly debilitating cognitive deficits of schizophrenia, which are thought to result from abnormalities of brain development. It will be realized at the Institute of Functional Genomics in the “Neuroproteomics and signaling of neurodegenerative and psychiatric disorders” team under the supervision of Philippe Marin and Séverine Chaumont-Dubel.
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Camille Pujol. Le récepteur 5-HT6 et la dynamique de son réceptosome : rôle dans la différenciation neuronale et potentiel thérapeutique pour le traitement des troubles de spectre de l'autisme. Neurobiologie. Université Montpellier, 2018. Français. ⟨NNT : 2018MONTT059⟩. ⟨tel-02172742⟩

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