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NMDA receptors: diversity, molecular mechanisms and synaptic regulation.

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Pierre Paoletti Talk at the University of Cambridge 11 May 2015 Title: “NMDA receptors: diversity, molecular mechanisms and synaptic regulation’ The function of the human brain and its capacity for experience-dependent change hinges on the dynamics of chemical synapses. My team has a long-standing interest in studying the molecular principles underpinning the structure and function of chemical synapses. Specifically, our research focuses on NMDA receptors (NMDARs), a family of glutamate-gated ion channel receptors that are essential mediators of synaptic plasticity and for which dysfunction is implicated in a variety of neurological and psychiatric disorders, from schizophrenia to mental retardation and epilepsy. Using a multi-level approach, we are interested in understanding the molecular operation of NMDA Rs, identifying their subunit-specific pharmacological properties, and deciphering the biological consequences of their functional diversity. Recent studies from our team have contributed to the emerging view that NMDA Rs are particularly complex molecular machines, endowed with unique allosteric capacity and exquisitely sensitive to their native microenvironment. Understanding the impact of NMDAR diversity and complexity on normal and diseased function remains a key challenge. I will present current knowledge on the anatomical and functional diversity of NMDA Rs, their molecular architecture and structural mechanisms, and the recent identification of key regions that allosterically control their subunit-specific gating and pharmacological profile. I will also present results obtained with genetically-modified mice revealing how endogenous CNS modulators, such as zinc ions, interact with specific NMDAR populations and regulate excitatory synapses and behavior. Finally, I will briefly discuss how information about NMDAR regulation may translate into the design of novel therapeutic agents.

Selection of recent publications Gielen et al. (2008) Structural rearrangements of NR1 /NR2A NMDA receptors during allosteric inhibition. Neuron, 57, 80-93. Gielen et al. (2009) Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature, 459, 703-707. Nozaki et al. (2011) Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit. Nature Neuroscience, 14, 1017-1082. Mony et al. (2011) Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines. EMBO Journal, 30, 3134-3146. Zhu et al. (2013) Nature Structural & Molecular Biology, 20(4):477-85. Paoletti P et al. (2013) NMDA receptor subunit diversity: impact of receptor properties, synaptic plasticity and disease. Nature Reviews Neuroscience, 14, 383-400. (Review) Zhu et al. (2014) Genetically encoding a light switch in an ionotropic glutamate receptor reveals subunit-specific interfaces. Proc. Nat. Acad. Sci. (USA), 111, 6081-6. Stroebel et al. (2014) Controlling NMDA receptor subunit composition using ectopic retention signals. Journal of Neuroscience, 34, 16630-6. Vergnano et al. (2014) Zinc dynamics and action at excitatory synapses. Neuron, 82, 1101-1114.

This talk is part of the Adrian Seminars in Neuroscience series.

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