Team Philippe MARIN

The serotonin 5-HT₆ receptor plays a key role in neuronal development and is a promising target for the treatment of cognitive deficits associated with neurodevelopmental disorders. In humans, the 5-HT₆ receptor has been implicated in the pathogenesis of neurological and psychiatric disorders, including dementia, psychosis and autism spectrum disorders (ASD). In mice, genetic inactivation of the receptor induces behavioral deficits similar to those observed in models of ASD. The molecular mechanisms underlying the control of neuronal development and cognition by the 5-HT₆ receptor remain poorly characterized. In addition to its canonical coupling to the Gs protein, the 5-HT₆ receptor engages the mTOR pathway, which underlies the cognitive deficits observed in mouse models of schizophrenia. However, there is also evidence that the receptor may engage other signaling pathways, depending on its developmental stage and subcellular localization.

Indeed, its subcellular localization is dynamic and varies during development. During the first ten days after birth, it is predominantly expressed at the membrane of cell bodies. In adults, however, it is mainly found in the primary cilia of neurons and astrocytes, especially at axo-ciliary synapses, where it controls histone expression, epigenetic modifications and chromatin structure. Using state-of-the-art omics approaches in embryonic stem cell models that we are developing, this research project aims to address 3 issues

• Identification of receptor partners in different cellular compartments during development
• Identify signaling pathways associated with the receptor in different cellular compartments during development.
• Identify epigenetic modifications involved in the regulation of gene expression by the ciliary 5-HT₆ receptor in a physiological or pathological context.