title: Zinc dynamics and action at excitatory synapses.
abstract: Decades after the discovery that ionic zinc is present at high levels in glutamatergic synaptic vesicles, where, when, and how much zinc is released during synaptic activity remains highly controversial. Here we provide a quantitative assessment of zinc dynamics in the synaptic cleft and clarify its role in the regulation of excitatory neurotransmission by combining synaptic recordings from mice deficient for zinc signaling with Monte Carlo simulations. Ambient extracellular zinc levels are too low for tonic occupation of the GluN2A-specific nanomolar zinc sites on NMDA receptors (NMDARs). However, following short trains of physiologically relevant synaptic stimuli, zinc transiently rises in the cleft and selectively inhibits postsynaptic GluN2A-NMDARs, causing changes in synaptic integration and plasticity. Our work establishes the rules of zinc action and reveals that zinc modulation extends beyond hippocampal mossy fibers to excitatory SC-CA1 synapses. By specifically moderating GluN2A-NMDAR signaling, zinc acts as a widespread activity-dependent regulator of neuronal circuits.
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), F-75005 Paris, France; Inserm, U1024, F-75005 Paris, France; CNRS, UMR 8197, F-75005 Paris, France.
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Vergnano
authors.affiliation: Université de Bordeaux, Institut Interdisciplinaire de Neurosciences, F-33000 Bordeaux, France; CNRS UMR 5297, F-33000 Bordeaux, France.
authors.forename: Nelson
authors.initials: N
authors.lastname: Rebola
authors.affiliation: UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Leonid P
authors.initials: LP
authors.lastname: Savtchenko
authors.affiliation: Université de Bordeaux, Institut Interdisciplinaire de Neurosciences, F-33000 Bordeaux, France; CNRS UMR 5297, F-33000 Bordeaux, France.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Pinheiro
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), F-75005 Paris, France; Inserm, U1024, F-75005 Paris, France; CNRS, UMR 8197, F-75005 Paris, France.
authors.forename: Mariano
authors.initials: M
authors.lastname: Casado
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, CNRS, INSERM, 67404 Illkirch, France.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Rusakov
authors.affiliation: Université de Bordeaux, Institut Interdisciplinaire de Neurosciences, F-33000 Bordeaux, France; CNRS UMR 5297, F-33000 Bordeaux, France. Electronic address: mulle@u-bordeaux2.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
authors.affiliation: Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), F-75005 Paris, France; Inserm, U1024, F-75005 Paris, France; CNRS, UMR 8197, F-75005 Paris, France. Electronic address: pierre.paoletti@ens.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Paoletti
mesh_terms: D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009010:Monte Carlo Method; D009474:Neurons / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D015032:Zinc