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J. Neurosci. 21 (20): 8015-8025

Copyright © 2001 by the Society for Neuroscience.

The Journal of Neuroscience, October 15, 2001, 21(20):8015-8025

Induction of Mossy Fiberright-arrow CA3 Long-Term Potentiation Requires Translocation of Synaptically Released Zn2+

Yang Li1, Christopher J. Hough2, Christopher J. Frederickson3, 4, and John M. Sarvey1

Departments of 1 Pharmacology and 2 Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, and 3 NeuroBioTex, Inc. and 4 Departments of Biomedical Engineering and Anatomy and Neuroscience, The University of Texas Medical Branch, Galveston, Texas 77550

The mammalian CNS contains an abundance of chelatable Zn2+ sequestered in the vesicles of glutamatergic terminals. These vesicles are particularly numerous in hippocampal mossy fiber synapses of the hilar and CA3 regions. Our recent observation of frequency-dependent Zn2+ release from mossy fiber synaptic terminals and subsequent entry into postsynaptic neurons has prompted us to investigate the role of synaptically released Zn2+ in the induction of long-term potentiation (LTP) in field CA3 of the hippocampus. The rapid removal of synaptically released Zn2+ with the membrane-impermeable Zn2+ chelator CaEDTA (10 mM) blocked induction of NMDA receptor-independent mossy fiber LTP by high-frequency electrical stimulation (HFS) in rat hippocampal slices. Mimicking Zn2+ release by bath application of Zn2+ (50-100 µM) without HFS induced a long-lasting potentiation of synaptic transmission that lasted more than 3 hr. Moreover, our experiments indicate the effects of Zn2+ were not attributable to its interaction with extracellular membrane proteins but required its entry into presynaptic or postsynaptic neurons. Co-released glutamate is also essential for induction of LTP under physiological conditions, in part because it allows Zn2+ entry into postsynaptic neurons. These results indicate that synaptically released Zn2+, acting as a second messenger, is necessary for the induction of LTP at mossy fiberright-arrowCA3 synapses of hippocampus.

Key words: zinc; long-term potentiation; CA3; hippocampus; CaEDTA; mossy fiber; plasticity; Na-pyrithione; Newport Green; synaptic transmission

Copyright © 2001 Society for Neuroscience  0270-6474/01/21208015-11$05.00/0

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J. Ceccom, H. Halley, S. Daumas, and J. M. Lassalle (2014)
Learn. Mem. 21, 287-297
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Inhibitory effect of zinc on glucose-stimulated zinc/insulin secretion in an insulin-secreting {beta}-cell line.
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Exp Physiol 98, 1301-1311
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Differential needs of zinc in the CA3 area of dorsal hippocampus for the consolidation of contextual fear and spatial memories.
J. Ceccom, E. Bouhsira, H. Halley, S. Daumas, and J. M. Lassalle (2013)
Learn. Mem. 20, 348-351
   Abstract »    Full Text »    PDF »
Synaptic Zn2+ Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis.
T. Perez-Rosello, C. T. Anderson, F. J. Schopfer, Y. Zhao, D. Gilad, S. R. Salvatore, B. A. Freeman, M. Hershfinkel, E. Aizenman, and T. Tzounopoulos (2013)
J. Neurosci. 33, 9259-9272
   Abstract »    Full Text »    PDF »
Vesicular Zinc Regulates the Ca2+ Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals.
N. Lavoie, D. V. Jeyaraju, M. R. Peralta III, L. Seress, L. Pellegrini, and K. Toth (2011)
J. Neurosci. 31, 18251-18265
   Abstract »    Full Text »    PDF »
The Neurophysiology and Pathology of Brain Zinc.
S. L. Sensi, P. Paoletti, J.-Y. Koh, E. Aizenman, A. I. Bush, and M. Hershfinkel (2011)
J. Neurosci. 31, 16076-16085
   Abstract »    Full Text »    PDF »
Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.
C. Sindreu, R. D. Palmiter, and D. R. Storm (2011)
PNAS 108, 3366-3370
   Abstract »    Full Text »    PDF »
Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation.
A. M. Grabrucker, M. J. Knight, C. Proepper, J. Bockmann, M. Joubert, M. Rowan, G. U. Nienhaus, C. C. Garner, J. U. Bowie, M. R. Kreutz, et al. (2011)
EMBO J. 30, 569-581
   Abstract »    Full Text »    PDF »
Pathway-Specific Utilization of Synaptic Zinc in the Macaque Ventral Visual Cortical Areas.
N. Ichinohe, A. Matsushita, K. Ohta, and K. S. Rockland (2010)
Cereb Cortex 20, 2818-2831
   Abstract »    Full Text »    PDF »
Spike-timing-dependent plasticity in hippocampal CA3 neurons.
S. Astori, V. Pawlak, and G. Kohr (2010)
J. Physiol. 588, 4475-4488
   Abstract »    Full Text »    PDF »
Zinc transporter 3 is involved in learned fear and extinction, but not in innate fear.
G. Martel, C. Hevi, O. Friebely, T. Baybutt, and G. P. Shumyatsky (2010)
Learn. Mem. 17, 582-590
   Abstract »    Full Text »    PDF »
Free zinc ions outside a narrow concentration range are toxic to a variety of cells in vitro.
R. A. Bozym, F. Chimienti, L. J. Giblin, G. W. Gross, I. Korichneva, Y. Li, S. Libert, W. Maret, M. Parviz, C. J. Frederickson, et al. (2010)
Experimental Biology and Medicine 235, 741-750
   Abstract »    Full Text »    PDF »
Activity-Dependent Release of Endogenous BDNF From Mossy Fibers Evokes a TRPC3 Current and Ca2+ Elevations in CA3 Pyramidal Neurons.
Y. Li, G. Calfa, T. Inoue, M. D. Amaral, and L. Pozzo-Miller (2010)
J Neurophysiol 103, 2846-2856
   Abstract »    Full Text »    PDF »
Zn2+ Activates Large Conductance Ca2+-activated K+ Channel via an Intracellular Domain.
S. Hou, L. E. Vigeland, G. Zhang, R. Xu, M. Li, S. H. Heinemann, and T. Hoshi (2010)
J. Biol. Chem. 285, 6434-6442
   Abstract »    Full Text »    PDF »
Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus.
L. Besser, E. Chorin, I. Sekler, W. F. Silverman, S. Atkin, J. T. Russell, and M. Hershfinkel (2009)
J. Neurosci. 29, 2890-2901
   Abstract »    Full Text »    PDF »
Enhanced Plasticity in Zincergic, Cortical Circuits after Exposure to Enriched Environments.
A. S. Nakashima and R. H. Dyck (2008)
J. Neurosci. 28, 13995-13999
   Abstract »    Full Text »    PDF »
pH-Dependent Inhibition of Kainate Receptors by Zinc.
D. D. Mott, M. Benveniste, and R. J. Dingledine (2008)
J. Neurosci. 28, 1659-1671
   Abstract »    Full Text »    PDF »
Zinc Potentiates Neuronal Nicotinic Receptors by Increasing Burst Duration.
B. Hsiao, K. B. Mihalak, K. L. Magleby, and C. W. Luetje (2008)
J Neurophysiol 99, 999-1007
   Abstract »    Full Text »    PDF »
Evidence That the ZNT3 Protein Controls the Total Amount of Elemental Zinc in Synaptic Vesicles.
D. H. Linkous, J. M. Flinn, J. Y. Koh, A. Lanzirotti, P. M. Bertsch, B. F. Jones, L. J. Giblin, and C. J. Frederickson (2008)
Journal of Histochemistry & Cytochemistry 56, 3-6
   Abstract »    Full Text »    PDF »
Extracellular chelation of zinc does not affect hippocampal excitability and seizure-induced cell death in rats.
N. Lavoie, M. R. Peralta III, M. Chiasson, K. Lafortune, L. Pellegrini, L. Seress, and K. Toth (2007)
J. Physiol. 578, 275-289
   Abstract »    Full Text »    PDF »
Intracellular Zinc Elevation Measured with a "Calcium-Specific" Indicator during Ischemia and Reperfusion in Rat Hippocampus: A Question on Calcium Overload.
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J. Neurosci. 26, 10430-10437
   Abstract »    Full Text »    PDF »
Synaptically released zinc gates long-term potentiation in fear conditioning pathways.
S. A. Kodirov, S. Takizawa, J. Joseph, E. R. Kandel, G. P. Shumyatsky, and V. Y. Bolshakov (2006)
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   Abstract »    Full Text »    PDF »
Vglut1 and ZnT3 co-targeting mechanisms regulate vesicular zinc stores in PC12 cells.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc.
C. E Clarke, E. L Veale, P. J Green, H. J Meadows, and A. Mathie (2004)
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   Abstract »    Full Text »    PDF »
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J. Nutr. 134, 1295-1298
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J.-Y. Lee, J.-H. Kim, S. H. Hong, J. Y. Lee, R. A. Cherny, A. I. Bush, R. D. Palmiter, and J.-Y. Koh (2004)
J. Biol. Chem. 279, 8602-8607
   Abstract »    Full Text »    PDF »
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E. Ohana, D. Segal, R. Palty, D. Ton-That, A. Moran, S. L. Sensi, J. H. Weiss, M. Hershfinkel, and I. Sekler (2004)
J. Biol. Chem. 279, 4278-4284
   Abstract »    Full Text »    PDF »
Zinc and Excitotoxic Brain Injury: A New Model.
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   Abstract »    PDF »
Heterogeneity of Ca2+-Permeable AMPA/Kainate Channel Expression in Hippocampal Pyramidal Neurons: Fluorescence Imaging and Immunocytochemical Assessment.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Boutons Containing Vesicular Zinc Define a Subpopulation of Synapses with Low AMPAR Content in Rat Hippocampus.
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   Abstract »    Full Text »    PDF »
Evidence for Chelatable Zinc in the Extracellular Space of the Hippocampus, But Little Evidence for Synaptic Release of Zn.
A. R. Kay (2003)
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   Abstract »    Full Text »    PDF »
Imaging Zinc: Old and New Tools.
C. Frederickson (2003)
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   Abstract »    Full Text »    PDF »
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Y. V. Li, C. J. Hough, and J. M. Sarvey (2003)
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   Abstract »    Full Text »    PDF »
Meeting of the minds: Metalloneurochemistry.
S. C. Burdette and S. J. Lippard (2003)
PNAS 100, 3605-3610
   Abstract »    Full Text »    PDF »
Honeycomb-Like Mosaic at the Border of Layers 1 and 2 in the Cerebral Cortex.
N. Ichinohe, F. Fujiyama, T. Kaneko, and K. S. Rockland (2003)
J. Neurosci. 23, 1372-1382
   Abstract »    Full Text »    PDF »
Zn2+ currents are mediated by calcium-permeable AMPA/Kainate channels in cultured murine hippocampal neurones.
Y. Jia, J.-M. Jeng, S. L Sensi, and J. H Weiss (2002)
J. Physiol. 543, 35-48
   Abstract »    Full Text »    PDF »
Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits.
S. Ueno, M. Tsukamoto, T. Hirano, K. Kikuchi, M. K. Yamada, N. Nishiyama, T. Nagano, N. Matsuki, and Y. Ikegaya (2002)
J. Cell Biol. 158, 215-220
   Abstract »    Full Text »    PDF »
Rapid, Experience-Dependent Changes in Levels of Synaptic Zinc in Primary Somatosensory Cortex of the Adult Mouse.
C. E. Brown and R. H. Dyck (2002)
J. Neurosci. 22, 2617-2625
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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