Zinc and Mossy Fiber LTP in the Mammalian Hippocampus: A Perspective

The role of zinc, one of the most abundant metals present in mammalian central nervous system, in various synaptic transmission and plasticity processes has been widely studied. The main target is the free or loosely bound zinc that is present in zinc-enriched synapses, including the important the synaptic system mossy fibers-CA3 pyramidal cells of the hippocampus. It is generally considered that zinc has a neuro modulatory role of this system. However, the role of zinc in Long-Term Potentiation (LTP) remains controversial. Here we present the different views about zinc requirement for expression of mossy fiber LTP, taking into account the different theories for the loci of induction and expression of mossy fiber LTP. Zinc is one of the most common transition metals in the central nervous system, and a large quantity of chelatable zinc is sequestered in synaptic vesicles, especially in the glutamatergic vesicles of hippocampal mossy fibers [1-4] Zinc is released into the synaptic cleft in a calciumdependent way, following high [5,6]of stimulation [4,7] and is taken up by zinc transport systems [2,8]. It has been shown that zinc is involved in several inhibitory and excitatory synaptic processes interacting with various neuro transmitter receptors and VoltageDependent Calcium Channels (VDCCs) [9-11]. Zinc may also enter postsynaptic neurons [12,13] and can have a neuro toxic effect when released at very high concentrations [14]. While most of the zinc present in the brain is contained in metallo proteins, a concentration of zinc of 10 300 μM may be obtained with the activation of the zinc-enriched mossy fiber synapses [15]. Several lines of evidence suggest that, at this concentrations, zinc plays a neuro modulatory role at hippocampal synapses, inhibiting glutamate release when acting at the pre synaptic site [4,16-18]. The pre synaptic action of vesicular zinc includes the inhibition of Nand P/Q types of VDCCs [19,20] and the activation of the potassium-activated ATP (KATP) channels [21,22]. The post synaptic actions of zinc include the inhibition of N-Methyl-D Aspartate (NMDA) [23], α-amino3-hydroxy-5-methyl4-izoxazolepropionic acid (AMPA) receptors [24-29], GABAA [30] and kainaite [31] receptors (Figure 1). However, in previous observations, it was shown that zinc enhanced AMPA and kainaite receptor responses [10]. A possible explanation for this discrepancy is the difference between the kinetics of the zinc chelators used in the referred experiments. In the presence of ZX1, a fast zinc chelator, it was observed that zinc chelation enhanced the response of AMPA receptors, while Ca EDTA (a slower zinc chelator) did not have the same effect [24]. Thus, some unanimity exists about the neuro modulatory role of zinc in the hippocampus, even in the mossy fibers and the postsynaptic zinc-enriched CA3 hippocampal neurons. On the other hand, the role of zinc in Long-Term Potentiation (LTP) of the mossy fibers remains controversial. LTP is a form of synaptic plasticity that may underlie learning and memory [25]. Mossy fiber LTP is a form of LTP that is independent of the activation of NMDA receptors and that is common in zinc-enriched mossy fiber synapses [32,33]. Despite the large number of studies about mossy fiber LTP, some controversy remains about the role of zinc in its induction and expression (Figure 2). This controversy is sustained by different experimental observations that supports [34,7] or opposes [34,35] the idea that zinc is necessary for mossy fiber LTP induction. It was proposed that the physiological action of zinc may depend on its effective concentration and the distance from the release site, for example, at a specific synapse, zinc might facilitate local and depress surrounding synapses [21]. However, the main reason for these contradictory results is the difference between the experimental approaches used in these studies. For instance, the application of low concentrations of the impairment zinc chelator Ca-EDTA did not affect mossy fiber LTP, while highest Ca-EDTA concentrations blocked LTP induction [34,7]. The application of membrane-per meant chelators as TFL-Zn and TPEN also gave contradictory results [26,35]. It was observed that the application of ZX1, which rapidly sequesters zinc, inhibits the increase of NMDA receptor currents after LTP induction [36]. In contrast, the application of Ca-EDTA did not have the same effect. It was also shown that mossy fiber LTP induction with high-frequency stimulation was significantly impaired by ZX1, which seems to Zinc and Mossy Fiber LTP in the Mammalian Hippocampus: A Perspective