Abstract
The serotonin (5-HT)6receptor is a Gs-coupled receptor exclusively expressed in the central nervous system. Highest receptor densities are found in brain regions implicated in mnemonic functions where the receptor is primarily but not exclusively locatedin the primary cilium of neurons. The 5-HT6receptor continues to raise particular interest for neuropharmacologists,given the pro-cognitive effects of antagonistsin a wide range of cognitive impairment paradigms in rodents and human. The 5-HT6receptor also finely controls key neuro-developmental processes including neuron migration and differentiation. However, itsinfluence upon neurodevelopment and cognition is not solely mediated by its coupling to the Gs-adenylyl cyclase pathway, suggestingalternative signal transduction mechanisms. This prompted studies aimed at characterizing the receptor interactome that identified 125 candidate receptor partners, making the 5-HT6receptor one of the G protein-coupled receptors with the most extensivelycharacterized interactome. These studies showed that the receptor localization at the plasma membrane and, consequently, its signal transduction, arefinely modulated by several receptor partners. They demonstrated that prefrontal 5-HT6receptorsengage the mTOR pathway to compromise cognition in neurodevelopmental models of schizophrenia, and a role of the 5-HT6-mTORpathway in temporal epilepsy.Finally, they revealed that the receptor activates Cdk5 signalingin an agonist-independent manner through a mechanism involving receptor phosphorylation by the associated Cdk5 and highlighted its key rolein the migration ofneurons and neurite growth. These new receptor-operated signalingmechanisms should be considered inthefuture development of drugs acting on5-HT6receptors