title: AMPA receptor inhibition by synaptically released zinc.
abstract: The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Bopanna I
authors.initials: BI
authors.lastname: Kalappa
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Charles T
authors.initials: CT
authors.lastname: Anderson
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Jacob M
authors.identifier: http://orcid.org/0000-0002-8004-3769
authors.initials: JM
authors.lastname: Goldberg
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15261; Department of and Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261 thanos@pitt.edu.
authors.forename: Thanos
authors.initials: T
authors.lastname: Tzounopoulos
mesh_terms: D000818:Animals; D017626:Cochlear Nucleus / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006624:Hippocampus / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009473:Neuronal Plasticity; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D009435:Synaptic Transmission; D015032:Zinc / Q000502:physiology*
chemical_list: D018091:Receptors, AMPA; D015032:Zinc
keywords: AMPA receptors; ZnT3; auditory; synaptic plasticity; zinc