CV Science

Michèle Darmon PhD Neuroscience, Serotonin Receptor Pharmacology and Trafficking

Course and current status

Dr Darmon received her Ph.D from Université Denis Diderot in Paris in 1990, after undergraduate training in Ecole Normale Supérieure (Cachan), and a master degree at Pasteur Institute. Her research focuses on the molecular biology of the serotoninergic system. During her Ph.D, in CNRS at Gif-sur-Yvette, she identified the gene encoding tryptophan hydroxylase, the enzyme that controls the synthesis of serotonin and joined INSERM as a permanent investigator in 1988. Then, she investigated the molecular bases for the targeting of serotonin receptors in neurons, and received her HDR from Université Denis Diderot. She is now a team leader in the Center for Psychiatry and Neuroscience (Paris). Her team (Cellular biology and molecular pharmacology of central receptors ) is involved in the molecular mechanisms of receptor trafficking, targeting and localization.

Scientific summary

The aim of the team is to characterize new pharmaceutical in the field of neurodegenerative diseases and psychiatry. Our approach relies on the observation that neurons are highly polarized cells with many compartments dendrites, dendritic spines, axons and soma. The localization of a receptor in a specialized compartment of the neuron conditions its function and its interaction with intracellular transducing pathways.

The project of the team consists in the characterization of the mechanisms implicated in the traffic of neuronal receptors. The project is centered on the mechanisms of receptor traffic (i) during their targeting to their appropriate localization in neurons [1, 2] and (ii) after acute or chronic stimulation by a ligand, as well as the functional consequences on receptor coupling. Our main topic is focused on the mechanisms of receptor trafficking with a particular interest for histaminergic and serotoninergic receptors that have been particularly studied by the members of the team. These receptors are implicated in the mode of action of several psycho-active drugs used in clinics and play a role in neuronal and psychiatric pathologies, such as depression and schizophrenia.
One part of the project explores the adaptative mechanisms that take place in neurons after a prolonged treatment, notably with the effect of antidepressant treatment on the desensitization and internalization of the serotonin 5-HT1A receptor [3]. We also currently investigate the role of Yif1B, a partner of the 5-HT1A receptor implicated in its dendritic localization [4, 5]. In particular we analyze the phenotype of a Yif1B KO mouse that we generated with regards of anxiety and depression behavioural tests. One hypothesis we made studying the traffic of the 5-HT1B receptor [6] is that pharmaco-resistance may result from a mislocalization of a receptor and/or a miscoupling after a chronic treatment, which could explain the loss of response to a drug.
In addition the team explores the mechanisms of targeting of other receptors: serotonin 5-HT3A and 5-HT3B [7], Histamine H3 short or long isoform [8, 9] and the orphan receptor GPR88 [10], which all present some particularities of targeting.
This project will help develop new paradigms in the field of adaptative mechanisms occurring after prolonged pharmacological treatments and the development of pharmaco-resistance.

Selected references of the team

1. Emerit M.B., Baranowski C., Diaz J., Martinez A., Areias J., Alterio J., Masson J., Boué-Grabot E. and Darmon M.  A new mechanism of receptor targeting by interaction between two classes of ligand-gated ion channels. J Neurosci, 2016, 36(5):1456-70
2. Massart R., Mignon V., Stanic J., Munoz-Tello P., Becker J.A.J., Kieffer B.L., Darmon M., Sokoloff P. and Diaz J. Developmental and adult expression patterns of the G protein-coupled receptor GPR88 in the rat: establishment of a dual nuclear-cytoplasmic localization. J Comp Neurol, doi: 10.1002/cne.23991.
3. Doly S., Shirvani H., Gäta G., Frank J. Meye F.J., Emerit M.B. , Enslen H., Achour L., Pardo-Lopez L., Seung-Kwon Yang  S-K, Armand V., Gardette R., Giros B., Gassmann M., Bettler B., Mameli M., Darmon M., Marullo S. GABAB receptor cell surface export is controlled by an endoplasmic reticulum gatekeeper, 2016 Mol Psychiatry. 2016, 21(4):480-90.
4. Alterio J., MassonJ., Diaz J., Chachlaki K., Salman H., Areias J., Al Awabdh S., Emerit M.B. and Darmon M. Yif1B is involved in the anterograde traffic pathway and the Golgi architecture. 2015, 16(9):978-93
5. Bouaziz E, Emerit MB, Vodjdani G, Gautheron V, Hamon M, Darmon M, Masson J. Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1A Serotonin Receptor. 2014. J Neurosci 34:282-294.
6. Al Awabdh S. , Miserey-Lenkei S., Bouceba T., Kano F., Marinach-Patrice C., Masson J., Hamon M., Emerit M.B., Darmon M. A new vesicular scaffolding complex mediates the G-protein-coupled 5-HT1A receptor targeting to neuronal dendrites. J Neurosci. 2012 Oct 10;32(41):14227-14241.
7. D. Carrel, A. Simon, M. B. Emerit, I. Rivals, C. Leterrier, M. Biard, M. Hamon, M. Darmon* and Z. Lenkei*: Axonal targeting of the 5-HT1B serotonin receptor relies on structure-specific constitutive activation. Traffic. 2011;12(11):1501-20. *co last authors
8. Carrel D., Masson J., Al Awabdh S..., Borg Capra C., Lenkei Z., Hamon M., Emerit M. B. and Darmon M. (2008) Targeting of the 5-HT1A serotonin receptor to neuronal dendrites is mediated by Yif1B. J Neurosci, 28:8063-8073.