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

Induction of Mossy FiberCA3 Long-Term Potentiation Requires Translocation of Synaptically Released Zn²⁺

Yang Li¹, Christopher J. Hough², Christopher J. Frederickson^{3, 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 fiberCA3 synapses of hippocampus.

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

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

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