Mossy fiber Zn2+ spillover modulates heterosynapticN-methyl-d-aspartate receptor activity in hippocampal CA3 circuits

Abstract

Although Zn2+ is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2+ indicator ZnAF-2, the spatiotemporal dynamics of Zn2+ was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2+ was immediately elevated in the stratum lucidum, followed by a mild increase in the stratum radiatum adjacent to the stratum lucidum, but not in the distal area of stratum radiatum. The Zn2+ increase was insensitive to a non–N-methyl-d-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca2+-free medium, suggesting that Zn2+ is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring stratum radiatum. Electrophysiological analyses revealed that NMDA receptor–mediated synaptic responses in CA3 proximal stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn2+-chelating agent. Thus, Zn2+ serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experience-dependent non-Hebbian modulation of synaptic plasticity.

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

“…Indeed, the excessive release of copper due to prolonged or inappropriate NMDA receptor activation would prove harmful to neurons, analogous to the role proposed for zinc during ischemic brain injury (34). In this case, spillover of copper from excitatory synapses could then result in the inhibition of heterosynaptic GABA receptors and the creation of a runaway circuit with excitotoxic consequences, as may occur with zinc (35). Experimental and clinical studies reveal that hypoxic͞ischemic encephalopathy in newborn infants results in neuronal excitotoxicity, including seizures and subsequent neurodegeneration triggered by a profound disruption in the function of glutamate synapses (36).…”

Essential Role for Zinc-Triggered p75NTRActivation in Preconditioning Neuroprotection

“…Although CaEDTA effects are likely mediated by removal of free zinc, we cannot completely rule out the possibility that calcium release from CaEDTA after zinc binding additionally contributes to the reversal of ischemic PC. However, this change may not have significant pathophysiological effects because the upper limit of extracellular calcium concentration change may be Ͻ30 M (1.5% of 2 mM normal calcium), based on the estimation that the peak zinc concentration after release is at most 30 M, probably much less (Ueno et al, 2002;Frederickson et al, 2006). .…”

A phenol-based compartmental ligand as a potential chemosensor for zinc(ii) cations

“…1 Hence the development of selective zinc chemosensors is of great importance for tracking the Zn 2+ status in biological systems. 2 Fluorescence chemosensors based on photoinduced electron transfer (PET), 3 intramolecular charge transfer (ICT), 4 excited-state intramolecular proton transfer (ESIPT), 5 and fluorescence resonance energy transfer (FRET) mechanisms have been developed for this purpose in the past years. 2,[6][7][8][9][10] Nevertheless, none of them completely satisfies the criteria for a biosystemoriented chemosensor.…”