Rapid Translocation of Zn²⁺From Presynaptic Terminals Into Postsynaptic Hippocampal Neurons After Physiological Stimulation

Abstract

Zn(2+) is found in glutamatergic nerve terminals throughout the mammalian forebrain and has diverse extracellular and intracellular actions. The anatomical location and possible synaptic signaling role for this cation have led to the hypothesis that Zn(2+) is released from presynaptic boutons, traverses the synaptic cleft, and enters postsynaptic neurons. However, these events have not been directly observed or characterized. Here we show, using microfluorescence imaging in rat hippocampal slices, that brief trains of electrical stimulation of mossy fibers caused immediate release of Zn(2+) from synaptic terminals into the extracellular microenvironment. Release was induced across a broad range of stimulus intensities and frequencies, including those likely to induce long-term potentiation. The amount of Zn(2+) release was dependent on stimulation frequency (1-200 Hz) and intensity. Release of Zn(2+) required sodium-dependent action potentials and was dependent on extracellular Ca(2+). Once released, Zn(2+) crosses the synaptic cleft and enters postsynaptic neurons, producing increases in intracellular Zn(2+) concentration. These results indicate that, like a neurotransmitter, Zn(2+) is stored in synaptic vesicles and is released into the synaptic cleft. However, unlike conventional transmitters, it also enters postsynaptic neurons, where it may have manifold physiological functions as an intracellular second messenger.

Late Calcium EDTA Rescues Hippocampal CA1 Neurons from Global Ischemia-Induced Death

“…Because the delayed rise in Zn 2ϩ may occur, at least in part, via GluR2-lacking AMPARs (Yin et al, 2002), CaEDTA would prevent Zn 2ϩ entry into CA1 neurons. Although not addressed by the present study, an attractive hypothesis is that early CaEDTA depletes extracellular Zn 2ϩ [and intracellular Zn 2ϩ , which leeches out of CA1 neurons as extracellular Zn 2ϩ is depleted (Li et al, 2001)] and thereby ultimately inhibits activity of REST, a nine zinc finger transcription factor that represses neuralspecific targets, including GluR2. By blocking cytochrome c release, a key step g-i) and experimental gerbils subjected to global ischemia ( j-l) or to global ischemia followed by CaEDTA (300 mM, i.c.v.…”

“…Within neurons, Zn 2ϩ exists as a functionally important component of metalloenzymes and zinc finger-containing transcription factors. Synaptically released Zn 2ϩ may be essential for long-term potentiation induction at CA3 synapses (Lu et al, 2000;Vogt et al, 2000;Li et al, 2001). Accordingly, Zn 2ϩ -deficient rats, monkeys, and humans exhibit cognitive impairment (Henkin et al, 1975;Golub et al, 1995;Lu et al, 2000).…”

Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvβ1.1

“…20,25,40,54,56,57). The location of this ion and its release pattern have been established across the brain by use of Zn 2ϩ fluoro-phores, radiolabeled Zn 2ϩ , and selective chelators (20,21,30,35,58,63). In particular, Zn 2ϩ is released from mossy fiber terminals in the hippocampus (4,61,64).…”

Importance of zinc in the elderly: the ZENITH study

“…Zn is found in the presynaptic vesicles of glutamatergic neurons, which use glutamate as a transmitter. The role of Zn in these neurons is controversial but may include participation in the storage, release and uptake of glutamate, and modulation of glutamate receptors (Li et al, 2001). Zn can act as a neuromodulator or neurotransmitter (Harrison & Gibbsons, 1994).…”