Hippocampal mossy fiber calcium transients are maintained during long-term potentiation and are inhibited by endogenous zinc

The hippocampal mossy fiber long-term potentiation (LTP) is an N-methyl-D-aspartate (NMDA) receptor-independent form of long-lasting synaptic plasticity characteristic of the zinc-enriched mossy fiber synapses. Its expression is generally considered to have a presynaptic locus and to be mediated by a persistent increase of evoked transmitter release. Because the release process is calcium-dependent, the observed increase in synaptic efficacy could be due to a persistent modification of presynaptic calcium mechanisms, triggered by the large calcium influx associated with long-term potentiation induction. Alternatively. it might be caused by an enhancement in the sensitivity to calcium of some components of the synaptic vesicle release system, following the large intraterminal calcium accumulation. We investigated the first hypothesis by measuring presynaptic Fura-2 calcium signals associated with electrically induced mossy fiber long-term potentiation. We have observed that like residual calcium, single presynaptic calcium changes are not enhanced during the maintenance phase of mossy fiber long-term potentiation. This result supports the idea that this form of long-term potentiation may be mediated by persistent changes of some process occurring after calcium entry. It has been established that voltage-dependent calcium channels are inhibited by zinc and that endogenous zinc is released in a calcium-dependent way following intense mossy fiber activation. Because there is evidence that at these synapses zinc is also released following single electrical stimulation, we investigated the effect of endogenous zinc on single presynaptic calcium signals and on field potentials associated with mossy fiber LTP. We have observed that this form of UP could be induced in the presence of the permeant heavy metal chelator N,N,N',N"-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and that application of this chelator, during LTP, caused an enhancement of the presynaptic calcium signals without affecting synaptic transmission. This enhancement is consistent with the idea that mossy fiber zinc, released following individual stimuli, inhibits presynaptic calcium mechanisms. (C) 2004 Elsevier B.V. All rights reserved.