Induction of mossy fiber -> CA3 long-term potentiation requires translocation of synaptically released Zn2+

The mammalian CNS contains an abundance of chelatable Zn2+ sequestered in t he vesicles of glutamatergic terminals. These vesicles are particularly num erous in hippocampal mossy fiber synapses of the hilar and CA3 regions. Our recent observation of frequency-dependent Zn2+ release from mossy fiber sy naptic terminals and subsequent entry into postsynaptic neurons has prompte d 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+ c helator CaEDTA (10 mM) blocked induction of NMDA receptor-independent mossy fiber LTP by high-frequency electrical stimulation (HFS) in rat hippocampa l slices. Mimicking Zn2+ release by bath application of Zn2+ (50-100 muM) w ithout HFS induced a long-lasting potentiation of synaptic transmission tha t lasted more than 3 hr. Moreover, our experiments indicate the effects of Zn2+ were not attributable to its interaction with extracellular membrane p roteins but required its entry into presynaptic or postsynaptic neurons. Co -released glutamate is also essential for induction of LTP under physiologi cal conditions, in part because it allows Zn2+ entry into postsynaptic neur ons. These results indicate that synaptically released Zn2+, acting as a se cond messenger, is necessary for the induction of LTP at mossy fiber-->CA3 synapses of hippocampus.