New lights on neurotransmission: from molecular optogenetics to excitatory glycine receptors, by Pierre Paoletti

Summary New lights on neurotransmission: from molecular optogenetics to excitatory glycine receptors

The function of the human brain and its remarkable capacity for information storage and experience-dependent change hinge on the dynamics of chemical synapses – main ‘contact points’ between neurons. My team has a long-standing interest in studying the molecular principles underpinning the structure and function of chemical synapses. Our research focuses primarily on glutamatergic synapses and ionotropic glutamate receptors (iGluRs), ion channel receptors that provide the bulk of excitatory neurotransmission in the CNS and that are essential mediators of synaptic plasticity. Recent years have witnessed major progress in our understanding of the structure, mechanisms and regulation of iGluRs, with highlights including the decoding of full-length receptor atomic structures and the identification of human iGluR genes as major risk factors for neuropsychiatric disorders. In this talk, I will present recent studies from our team covering various aspects of iGluR biology, with a special focus on NMDA receptors (NMDARs). Topics will include allosteric mechanisms, synaptic microenvironment, optogenetic pharmacology and novel types of neuronal NMDARs insensitive to glutamate but gated by glycine. Our approach is multiscale and bridge fields ranging from molecular and cellular neuroscience to protein engineering, synaptic physiology and behavior. Our work opens new vistas on the diversity and complexity of iGluR signaling and of neurotransmission in general, with potential implications in precision drug development.

Short Biography 

Pierre PAOLETTI is a researcher at INSERM and the current director of the Institute of Biology of the Ecole Normale Supérieure (IBENS, Paris), a joined ENS-CNRS-INSERM unit which gathers 30 research groups and >300 staff members in Genetics & Genomics, Cell & Developmental Biology, Ecology & Evolution, and Neuroscience.

After a PhD in Neuroscience and Molecular Pharmacology at the ENS & University Paris 6, Pierre Paoletti underwent postdoctoral training in ion channel biophysics at Columbia University in New York. In 2005, he established his own lab at the ENS working on various aspects of ionotropic glutamate receptors and excitatory neurotransmission. Key contributions include the identification of essential regions of NMDAR subunits controlling the receptor functional properties and allosteric mechanisms, uncovering novel binding sites for neuro-active compounds and discovery that endogenous zinc, which is highly enriched in the brain, is a potent and widespread modulator of neurocircuits and synaptic plasticity through its action on GluN2A-NMDARs. Together with colleagues in Paris, he also discovered that GluN3A-NMDARs form a novel type of excitatory glycine receptors in the brain, thus reshaping our understanding of NMDAR diversity and glycinergic neurotransmission. Pierre Paoletti and his team recently developed innovative approaches of molecular engineering to reprogram brain receptors to artificially respond to light, opening new avenues for interrogating their structure and function with unprecedented resolution.

Pierre Paoletti received the FENS Young Investigator Award in 2010, an ERC Advanced Grant Award in 2016, the Grand Prix Lamonica de Neurologie – Académie des Sciences in 2017, and is a member of the Academia Europaea.

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