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

被引:142
|
作者
Sindreu, Carlos [2 ]
Palmiter, Richard D. [1 ,3 ]
Storm, Daniel R. [2 ]
机构
[1] Univ Washington, Dept Biochem, Seattle, WA 98195 USA
[2] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
[3] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA
基金
美国国家卫生研究院;
关键词
signal transduction; synaptic zinc; CA3; cognition; SYNAPTICALLY RELEASED ZINC; LONG-TERM POTENTIATION; SYNAPSIN-I; MAP KINASE; MOSSY; MICE; ACTIVATION; INHIBITION; RECEPTORS; VESICLES;
D O I
10.1073/pnas.1019166108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:3366 / 3370
页数:5
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