Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.
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.
Departments of Pharmacology and Biochemistry and The Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Carlos
C
Sindreu
Richard D
RD
Palmiter
Daniel R
DR
Storm
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D027682:Cation Transport Proteins; D005089:Exocytosis; D006624:Hippocampus / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000502:physiology*; D026901:Membrane Transport Proteins; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal; D017729:Presynaptic Terminals / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C491177:Slc30a3 protein, mouse; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases; D015032:Zinc
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