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Flajolet is interested in the molecular and cellular mechanisms underlying neuronal signaling, both in healthy brains as well as in neurodegenerative diseases, with a focus on Alzheimer’s disease. He has studied several classes of signaling components including G protein–coupled receptors (GPCRs) and their regulatory factors, and protein kinases. Out of about 400 non-sensory GPCRs present in the human genome, about a fifth are still orphan, meaning that their natural ligands are not known. Furthermore, these 120 receptors are vastly uncharacterized: their coupling to secondary messengers is often not established, and their biological functions haven’t been uncovered. The phylogenetic clustering of some of these receptors, and the absence of strong similarities to other subfamilies of GPCRs, may indicate that entirely new biological functions and neurotransmitter systems will be discovered.

Flajolet has studied important and well characterized GPCRs, such as metabotropic glutamate, serotonin, and adenosine receptors, identifying novel signaling routes and regulatory proteins. In a search for key regulatory proteins, novel neuronal pathways, and possibly entirely new neurotransmitter systems, Flajolet’s current research is focused on orphan GPCRs that are enriched in the hippocampal formation, an important brain region responsible for learning and memory that is involved in, among other things, fact recollection and spatial memory formation. The two major goals of his research are to identify ligands (natural ones or pharmacological tools) for these orphan receptors and to uncover the functions of these receptors in vivo in the brain. Because of their localization in the brain, these receptors might be relevant for various mental disorders and diseases involving memory, neurogenesis, and developmental dysfunction in general. The putative novel neurotransmitter systems associated with these orphan GPCRs represent important untapped opportunities to develop new paradigms to better understand, and ideally treat, diseases of the central nervous system.