Labex EPIGENMED Montpellier, France

 Pathophysiology of synaptic transmission

 Laurent FAGNI

 IGF - UMR 5203/U 661

 141, rue de la Cardonille, 34396 Montpellier

Phone: +33 4 34 35 92 09

Email: laurent.fagni@igf.cnrs.fr

Website

One of the most important challenge of the XXIst century will be the discovery of efficient therapies against psychiatric and neurological disorders. To this end, a reasonable strategy is to improve our understanding of the brain and to identify best therapeutic targets. We follow this strategy by searching for molecular determinants that control the formation, function and plasticity of synaptic contacts, under physiological and pathological conditions. We focus on the structure, epigenetics and patho-physiological function of synaptic proteins controlling neurotransmitter receptors. We pay special attention to factors affecting the receptor subcellular targeting, membrane assembly, intracellular signaling and synaptic functions. We study those aspects in most prevalent brain disorders: mental retardation, autism, epilepsies and neurodegenerative (Parkinson's and Alzheimer's) diseases.

Keywords: Synapse, PDZ proteins, dendritic spines, plasticity, brain disorders

Main publications

• Perroy J, Prezeau L., De Waard M., Shigemoto R., Bockaert J., Fagni L. Selective blockade of P/Q-type calcium channels by the metabotropic glutamate receptor type 7 involves a phospholipase C pathway in neurons. J. Neurosci. 2000, 20: 7896-7904
• Ango F., Prézeau L., Muller T, Tu J.C., Xiao B., Worley P.F., Pin J.P., Bockaert J., Fagni L. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 2001, 411: 962-965
• Perroy J., El Far O., Bertaso F., Pin J.P., Betz H., Bockaert J., Fagni L. PICK1 is required for the control of synaptic transmission by the mglu7a receptor. EMBO J. 2002, 21: 2990 2999
• Roussignol, G., Ango, F., Romorini, S., Tu, J.C., Sala, C., Worley, P., Bockaert, J., Fagni, L. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J. Neurosci. 2005, 25: 3560-3570
• Sala, C., Roussignol, G, J. Meldolesi, L. Fagni. Key role of the PSD scaffold proteins, Shank and Homer, in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neuron, J. Neurosci. 2005, 25: 4587-4592
• Ster J., De Bock F., Guérineau N., Janossy A., Barrère-Lemaire S., Bos J.L., Bockaert J., Fagni L. Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons. Proc.. Natl. Acad. Sci., 2007, 104: 2519-2524
• Saglietti L., Dequidt C., Kamieniarz K., Rousset M-C, Valnegri P., Thoumine O., Beretta F., Fagni L., Choquet D., Sala C., Sheng M. and Passafaro M. Extracellular interaction between GluR2 and N-Cadherin in spine regulation. Neuron 2007, 54: 461-477
• Bertaso F, Zhang C, Scheschonka A, de Bock F, Fontanaud P, Marin P, Huganir RL, Betz H, Bockaert J, Fagni L, Lerner-Natoli M. PICK1 uncoupling from mGluR7a causes absence-like seizures. Nat. Neurosci. 2008, 111: 940-948
• Zhang CS*, Bertaso F*, Eulenburg V*, Lerner-Natoli M, Herin GA, Bauer L, Bockaert J, Fagni L, Betz H, Scheschonka A. Knock-in mice lacking the pdz-ligand motif of mglur7a show impaired pkc-dependent autoinhibition of glutamate release, spatial working memory deficits, and increased susceptibility to pentylenetetrazol. J. Neurosci. 2008, 28: 8604-14
• Durand, C. M., Perroy, J., Loll, F., Perrais, D., Fagni, L., Bourgeron, T., Montcouquiol, M., Sans, N. SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry 2012, 17: 71-84
• Moutin, E., Raynaud, F., Fagni, L., Perroy, J. GKAP-DLC2 interaction organizes postsynaptic scaffold complex to enhance synaptic NMDA receptor activity. J Cell Sci., 2012, 125:2030-40.
• Enora Moutin*, Fabrice Raynaud*, Jonathan Roger, Emilie Pellegrino,Vincent Homburger, Vincent Ollendorff, Joël Bockaert, Laurent Fagni and Julie Perroy.. Protein scaffold remodeling in space and time controls membrane receptor crosstalk and synaptic excitability. J. Cell Biol., 2012, 198: 251-263