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Pierre Paoletti

Glutamate Receptors and Excitatory Synapses

The function of the human brain and its capacity for experience-dependent change hinges on the dynamics of chemical synapses. Our 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 NMDA receptors (NMDARs), ion channel receptors that provide a key component of excitatory neurotransmission in the CNS and that are essential mediators of synaptic plasticity. NMDARs are also targets of strong therapeutic interest since their dysfunction is implicated in a variety of neurodevelopmental and neuropsychiatric disorders including schizophrenia, mental retardation and epilepsy. Studies from our team cover various aspects ranging from receptor structural and allosteric mechanisms, to subunit-specific pharmacology, origin and evolution of neurotransmitter specificity, dynamics of the synaptic microenvironment and impact of receptor signaling diversity on circuit function and behavior. Our approach is multiscale and bridges fields ranging from molecular and cellular neuroscience to protein engineering, molecular phylogeny, receptor biophysics, synaptic physiology, cellular imaging, optopharmacology and behavior. Our work aims at deciphering the complexity of neuronal communication. We are also attempting to translate information about the regulation of receptor and synapse function into the design of novel precision therapeutic strategies.

Paoletti P, Bellone C and Zhou Q. NMDA receptor subunit diversity: impact of receptor properties, synaptic plasticity and disease. Nature Reviews Neuroscience (2013) 14, 383-400.

Vergnano AM, Rebola N, Savtchenko LP, Pinheiro PS, Casado M, Kieffer BL, Rusakov DA, Mulle C and Paoletti P. Zinc dynamics and action at excitatory synapses. Neuron (2014), 82(5), 1101-14.

Klippenstein V, Hoppmann C, Ye S, Wang L, Paoletti P. Optocontrol of glutamate receptor gating and permeation by single side-chain photoisomerization. eLife (2017) 6, e25808.

Grand T, Abi Gerges S, David M, Diana MA, Paoletti P. Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nature Communications (2018), 9(1):4769.

Esmenjaud JB, Stroebel D, Chan K, Grand T, David M, Wollmuth L, Taly A, Paoletti P. An inter‐dimer allosteric switch controls NMDA receptor activity. EMBO Journal (2019), 38(2):e99894.

Paoletti P, CR Ellis-Davies G and Mourot A. Optical control of neuronal ion channels and receptors. Nature Reviews Neuroscience (2019), 20(9):514-532.

Tian M, Stroebel D, Piot L, David M, Ye S, Paoletti P. GluN2A and GluN2B NMDA receptors use distinct allosteric routes. Nature Communications (2021), 12(1):4709.

Bossi S*, Dhanasobhon D*, Ellis-Davies G.C.R, Frontera J, de Brito Van Velze M, Lourenco J, Murillo A, Lujan R, Casado M, Perez-Otano I, Bacci A, Popa D, Paoletti P#, Rebola N#. GluN3A excitatory glycine recpetors control adult cortical and amygdalar circuits. Neuron (2022), 110(15):2438-2454.e8. *Co-1st author #Co-senior author

Piot L , Heroven C*, Bossi S*, Zamith J, Malinauskas T, Johnson C, Wennagel D, Stroebel D, Charrier C, Aricescu A.R#, Mony L# and Paoletti P#. GluD1 binds GABA and controls inhibitory plasticity. Science (2023), 382(6677):1389-1394 *Co-second author #Co-senior author




Mechanism of long-distance allosteric transduction in NMDARs
Mechanism of long-distance allosteric transduction in NMDARs
Light-sensitive NMDARs using genetically-encoded unnatural AAs
Light-sensitive NMDARs using genetically-encoded unnatural AAs
Zinc action at excitatory synapses
Zinc action at excitatory synapses