Abstract
The establishment of neural circuits is a complex and finely regulated process. When this process is altered, neurodevelopmental pathologies such as schizophrenia or autism spectrum disorders can appear, for which treatment is insufficient to date. The serotonin 5-HT6 receptor is an interesting therapeutic target for the treatment of cognitive deficits associated with these pathologies. However, the mechanisms underlying its role in neurodevelopment are not fully understood. Indeed, the study of the functions of the 5-HT6 receptor in vivo is complicated so far, because its exact location in the central nervous system is still poorly known. This lack of knowledge results from the absence of specific antibodies allowing to perform immunostaining studies in vivo. My work allowed to overcome this problem and to carry out a complete mapping of the expression of the 5-HT6 receptor during development, thanks to the use of a knock-in mouse model expressing the 5-HT6 receptor tagged with a fluorescent label (GFP). This study made it possible to identify not only the structures but also the cell types which express the receptor. I was able to determine that the receptor is expressed very early in development, and that its expression persists into adulthood. It is found in projection neurons as well as in astrocytes, where it is predominantly located in the primary cilium, an organelle involved in various developmental phenomena including neuronal migration. Knock-out animals that no longer express the 5-HT6 receptor exhibit shortened cilia, indicating a role of the receptor in ciliary functions. Interestingly, I was able to show that this subcellular localization is strongly modified during the first 10 postnatal days, where the receptor is mainly relocated in the somatodendritic compartment. This relocation of the receptor to the soma seems essential for its interaction with some of its partners, such as GPRIN1. In vitro, the complex formed by GPRIN1 and the receptor promotes the complexification of dendritic arborization. My work demonstrated in vivo the interaction between GPRIN1 and the 5-HT6 receptor at the level of the somatic membrane of neurons, in postnatal mice brain slices. Eventually, I demonstrated that the pharmacological inhibition of the constitutive activity of the receptor by inverse agonist compounds during the postnatal period induces behavioral sociability deficits measured in adolescence. This suggests a critical role of the constitutive activity of the receptor specifically during the first days of postnatal neurodevelopment, when it is localized in the somatodendritic compartment. Thus, my thesis work made it possible to precisely characterize the location of the receptor during development, from the embryonic stage to the adulthood. A major discovery of my work is the dynamic relocation of the receptor from the cilium to the somatodendritic compartment during the postnatal period and the fact that the inhibition of the constitutive activity of the receptor during this period induces an alteration in social behaviour. This original observation could explain the key role played by the receptor at this critical period of neuronal development. This study forms a solid basis for future research on the functions of the 5-HT6 receptor during development and in adults and confirms its interest as a therapeutic target in the context of neurodevelopmental pathologies.