Neuron
Volume 71, Issue 6, 22 September 2011, Pages 1116-1126
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Article
Vesicular Zinc Promotes Presynaptic and Inhibits Postsynaptic Long-Term Potentiation of Mossy Fiber-CA3 Synapse

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Summary

The presence of zinc in glutamatergic synaptic vesicles of excitatory neurons of mammalian cerebral cortex suggests that zinc might regulate plasticity of synapses formed by these neurons. Long-term potentiation (LTP) is a form of synaptic plasticity that may underlie learning and memory. We tested the hypothesis that zinc within vesicles of mossy fibers (mf) contributes to mf-LTP, a classical form of presynaptic LTP. We synthesized an extracellular zinc chelator with selectivity and kinetic properties suitable for study of the large transient of zinc in the synaptic cleft induced by mf stimulation. We found that vesicular zinc is required for presynaptic mf-LTP. Unexpectedly, vesicular zinc also inhibits a form of postsynaptic mf-LTP. Because the mf-CA3 synapse provides a major source of excitatory input to the hippocampus, regulating its efficacy by these dual actions, vesicular zinc is critical to proper function of hippocampal circuitry in health and disease.

Highlights

► A zinc chelator, ZX1, inhibits presynaptic mf-LTP in WT mice ► Postsynaptic mf-LTP is evident in ZnT3−/− mice lacking synaptic vesicular zinc ► Dialysis of CA3 pyramid with BAPTA inhibits mf-LTP in ZnT3−/− but not WT mice ► A zinc chelator, ZX1, unmasks postsynaptic mf-LTP in rim1α mutant mice

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6

These authors contributed equally to this work

7

Present address: Department of Chemistry, 18-498, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

8

Present address: Department of Neurobiology, Campus Box 3676, Duke University Medical Center, Durham, NC 27710, USA