Abstract
Brain circuitry patterning is a complex, highly regulated process. Alteration of this process is affected gives rise to various neurodevelopmental disorders such as schizophrenia or Autism Spectrum Disorders (ASD), which are both characterized by a wide spectrum of deficits. Serotonin 6 receptor (5-HT6 receptor), which is known for its implication in neuronal migration process, has been identified as a key therapeutic target for the treatment of cognitive deficits observed in schizophrenia, but also in neurodegenerative pathologies such as Alzheimer's disease. However, the signalling mechanisms knowned to be activated by the 5-HT6 receptor do not explain its involvement in neurodevelopmental processes. My thesis project therefore aimed at characterizing the signalling pathways engaged by 5-HT6 receptor during neural development. A proteomic approach allowed me to show that the 5-HT6 receptor was interacting with several proteins playing crucial roles in neurodevelopmental processes such as Cdk5 or WAVE-1. I then demonstrated that, besides its role in neuronal migration, the 5-HT6 receptor was also involved in neurite growth through constitutive phosphorylation of 5-HT6 receptor at Ser350 by associated Cdk5, a process leading to an increase in Cdc42 activity. The second part of my work aimed at understanding the role of 5-HT6 receptor in dendritic spines morphogenesis, and the involvement of WAVE-1 and Cdk5 in this process. These results provide new insights into the control of neurodevelopemental processes by 5-HT6 receptor. Thus, 5-HT6 receptor appears to be a key therapeutic target for neurodevelopmental disorders by contributing to the development of cognitive circuitry related to the pathophysiology of ASD or schizophrenia.