title: Tonic zinc inhibits spontaneous firing in dorsal cochlear nucleus principal neurons by enhancing glycinergic neurotransmission.
abstract: In many synapses of the CNS, mobile zinc is packaged into glutamatergic vesicles and co-released with glutamate during neurotransmission. Following synaptic release, the mobilized zinc modulates ligand- and voltage-gated channels and receptors, functioning as an inhibitory neuromodulator. However, the origin and role of tonic, as opposed to phasically released, zinc are less well understood. We investigated tonic zinc in the dorsal cochlear nucleus (DCN), a zinc-rich, auditory brainstem nucleus. Our results show that application of a high-affinity, extracellular zinc chelator (ZX1) enhances spontaneous firing in DCN principal neurons (fusiform cells), consistent with inhibition of this neuronal property by tonic zinc. The enhancing effect was prevented by prior application of strychnine, a glycine receptor antagonist, suggesting that ZX1 interferes with zinc-mediated modulation of spontaneous glycinergic inhibition. In particular, ZX1 decreased the amplitude and the frequency of glycinergic miniature inhibitory postsynaptic currents in fusiform cells, from which we conclude that tonic zinc enhances glycinergic inhibitory neurotransmission. The observed zinc-mediated inhibition in spontaneous firing is present in mice lacking the vesicular zinc transporter (ZnT3), indicating that non-vesicular zinc inhibits spontaneous firing. Noise-induced increase in the spontaneous firing of fusiform cells is crucial for the induction of tinnitus. In this context, tonic zinc provides a powerful break of spontaneous firing that may protect against pathological run-up of spontaneous activity in the DCN.
authors: Department of Otolaryngology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.
authors: Tamara
authors: T
authors: Perez-Rosello
authors: Department of Otolaryngology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.
authors: Charles T
authors: CT
authors: Anderson
authors: Department of Otolaryngology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA.
authors: Cindy
authors: C
authors: Ling
authors: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors: Stephen J
authors: SJ
authors: Lippard
authors: Department of Otolaryngology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA 15261, USA. Electronic address: thanos@pitt.edu.
authors: Thanos
authors: T
authors: Tzounopoulos
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins; D002614:Chelating Agents / Q000494:pharmacology; D017626:Cochlear Nucleus / Q000166:cytology*; D004347:Drug Interactions; D005998:Glycine / Q000378:metabolism*; D018684:Glycine Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology; D013425:Sulfanilic Acids / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002614:Chelating Agents; D018684:Glycine Agents; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D011725:Pyridines; C491177:Slc30a3 protein, mouse; D013425:Sulfanilic Acids; C000609871:ZX1 chelating agent; D013331:Strychnine; D015032:Zinc; D005998:Glycine
keywords: Auditory brainstem; Dorsal cochlear nucleus; Glycinergic neurotransmission; Spontaneous firing; Vesicular zinc transporter; Zinc