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Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.

ABSTRACT: The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus-dependent memory.

SUBMITTER: Sindreu C

PROVIDER: S-EPMC3044399 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.

Sindreu Carlos C Palmiter Richard D RD Storm Daniel R DR

Proceedings of the National Academy of Sciences of the United States of America 20110118 8

The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK ...[more]

PMID: 21245308

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Project description:Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12-P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca(2+) for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca(2+) release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.

Dataset Information

Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.

Publications

Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.

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