Modelling zinc changes at the hippocampal mossy fiber synaptic cleft

Abstract

Zinc, a transition metal existing in very high concentrations in the hippocampal mossy fibers from CA3 area, is assumed to be co-released with glutamate and to have a neuromodulatory role at the corresponding synapses. The synaptic action of zinc is determined both by the spatiotemporal characteristics of the zinc release process and by the kinetics of zinc binding to sites located in the cleft area, as well as by their concentrations. This work addresses total, free and complexed zinc concentration changes, in an individual synaptic cleft, following single, short and long periods of evoked zinc release. The results estimate the magnitude and time course of the concentrations of zinc complexes, assuming that the dynamics of the release processes are similar to those of glutamate. It is also considered that, for the cleft zinc concentrations used in the model (≤ 1 μM), there is no postsynaptic zinc entry. For this reason, all released zinc ends up being reuptaken in a process that is several orders of magnitude slower than that of release and has thus a much smaller amplitude. The time derivative of the total zinc concentration in the cleft is represented by the difference between two alpha functions, corresponding to the released and uptaken components. These include specific parameters that were chosen assuming zinc and glutamate co-release, with similar time courses. The peak amplitudes of free zinc in the cleft were selected based on previously reported experimental cleft zinc concentration changes evoked by single and multiple stimulation protocols. The results suggest that following a low amount of zinc release, similar to that associated with one or a few stimuli, zinc clearance is mainly mediated by zinc binding to the high-affinity sites on the NMDA receptors and to the low-affinity sites on the highly abundant GLAST glutamate transporters. In the case of higher zinc release brought about by a larger group of stimuli, most zinc binding occurs essentially to the GLAST transporters, having the corresponding zinc complex a maximum concentration that is more than one order of magnitude larger than that for the high and low affinity NMDA sites. The other zinc complexes considered in the model, namely those formed with sites on the AMPA receptors, calcium and K channels and with ATP molecules, have much smaller contributions to the synaptic zinc clearance.

Intracellular Zn2+ transients modulate global gene expression in dissociated rat hippocampal neurons

“…These tool limitations do not provide definitive evidence that synaptic Zn 2+ is absent from dissociated cultures. In contrast, using a different detection system, a recent study observed release of Zn 2+ from stimulated cortical neurons and calculated the local synaptic Zn 2+ concentration as approximately 100 nM 25 , which is in accordance with previous estimates 15,16,42 . Although we could not definitively confirm the presence of synaptic Zn 2+ , we were able to rigorously define the resting cytosolic labile Zn 2+ concentration to be approximately 60 pM (using ZapCV2) to 110 pM (using FluoZin3 AM), and we observed a small transient rise in Zn 2+ to roughly 150 pM upon depolarization with KCl.…”

“…Electrophysiology studies in brain slices have demonstrated that Zn 2+ is released upon neuronal activation and modulates postsynaptic glutamate receptors 2,4,15 . Transient increases in Zn 2+ have been observed inside neurons after stimulation, possibly as a result of translocation of Zn 2+ from the synapse or release of Zn 2+ from intracellular stores 16–18 . Both synaptic and intracellular Zn 2+ signals contribute to regulation of short- and long-term plasticity in different areas of the brain 1,15,19,20 , and genetic or pharmacological manipulation of hippocampal Zn 2+ leads to learning and memory deficits in rodents 21–23 .…”

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

“…Most of the remaining labile, nominally unbound or weakly bound zinc in the brain is present in synaptic vesicles of a large population of excitatory glutamatergic neurons throughout the cerebral cortex, hippocampus, striatum, and auditory brainstem [ 10 , 11 , 12 ]. Zinc is concentrated within synaptic vesicles by zinc transporter 3 (ZnT3) [ 13 , 14 , 15 ] and is synaptically released in an activity-dependent manner, acting as a neuromodulator for a number of neurotransmitter receptors [ 16 , 17 , 18 , 19 , 20 ]. Additionally, zinc released at glutamatergic synapses can translocate into postsynaptic cells through calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) [ 21 , 22 , 23 ], voltage-gated calcium channels (VGCCs) [ 24 , 25 ], and N-methyl-D-aspartate receptors (NMDARs) [ 26 ], subsequently activating a number of physiological and pathophysiological signaling processes [ 19 ].…”

General Aspects of Metal Ions as Signaling Agents in Health and Disease

“…In the membrane of postsynaptic neurons, zinc ions can cause a number of excitatory or inhibitory reactions by interacting with different receptors, and the best-known targets are N-methyl-D-aspartate glutamate receptor (NMDAR) [ 107 , 119 ], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (APMAR) [ 120 , 121 ], or voltage-gated Ca 2+ channels [ 122 , 123 ]. The concentration of zinc ions in the postsynaptic nerve terminals is controlled by the ZnT-1 transporter activity; the expression of this transporter depends on the number of free zinc ions within the cell [ 124 ].…”