Zinc at glutamatergic synapses

doi:10.1016/j.neuroscience.2008.01.061

Neuroscience

Volume 158, Issue 1, 12 January 2009, Pages 126-136

https://doi.org/10.1016/j.neuroscience.2008.01.061 Get rights and content

Abstract

It has long been known that the mammalian forebrain contains a subset of glutamatergic neurons that sequester zinc in their synaptic vesicles. This zinc may be released into the synaptic cleft upon neuronal activity. Extracellular zinc has the potential to interact with and modulate many different synaptic targets, including glutamate receptors and transporters. Among these targets, NMDA receptors appear particularly interesting because certain NMDA receptor subtypes (those containing the NR2A subunit) contain allosteric sites exquisitely sensitive to extracellular zinc. The existence of these high-affinity zinc binding sites raises the possibility that zinc may act both in a phasic and tonic mode. Changes in zinc concentration and subcellular zinc distribution have also been described in several pathological conditions linked to glutamatergic transmission dysfunctions. However, despite intense investigation, the functional significance of vesicular zinc remains largely a mystery. In this review, we present the anatomy and the physiology of the glutamatergic zinc-containing synapse. Particular emphasis is put on the molecular and cellular mechanisms underlying the putative roles of zinc as a messenger involved in excitatory synaptic transmission and plasticity. We also highlight the many controversial issues and unanswered questions. Finally, we present and compare two widely used zinc chelators, CaEDTA and tricine, and show why tricine should be preferred to CaEDTA when studying fast transient zinc elevations as may occur during synaptic activity.

Section snippets

Localization of brain “chelatable zinc”

The divalent cation Zn²⁺ is the second most prevalent trace element in the body (after iron). It has myriad functional roles throughout the body and it has been known since the 1930s to be a vital part of a healthy diet. Although the vast majority (>95%) of zinc ions are trapped within proteins as structural or catalytic co-factors, in the mammalian brain there is a pool of zinc that is less tightly bound and that can be revealed by histochemical techniques, such as the Timm's sulfide-silver

Is zinc released during neuronal activity?

Because “chelatable zinc” is accumulated into synaptic vesicles that also contain the neurotransmitter glutamate, it has been surmised that zinc, together with glutamate, could be released in the extracellular medium during neuronal activity. Early studies in the 1980s showed that strong stimulation of the hippocampal MFs, which show the strongest zinc staining in the brain, elevates the concentration of zinc measured in the perfusate, suggesting that endogenous zinc can indeed be released from

Zinc targets at excitatory synapses

There are multiple mechanisms by which extracellular zinc could modulate fast excitatory glutamatergic transmission. Both ionotropic glutamate receptors (iGluRs) and glutamate transporters are sensitive to extracellular zinc (Smart et al 2004, Frederickson et al 2005). However, depending on the nature of the target, zinc may either boost or depress the synaptic response. In addition, the potency of zinc varies considerably between the different targets.

The best characterized synaptic zinc

Zinc in excitatory synaptic transmission and plasticity

As described above, at certain glutamatergic synapses of the forebrain, zinc fulfils most of the prerequisites for an endogenous modulator of synaptic transmission: presence of zinc inside synaptic vesicles and presence of multiple synaptic targets, most noticeably NMDARs. In addition, given the central importance of NMDARs in cognitive functions (learning and memory) as well as in numerous pathological states of the CNS (stroke, pain, schizophrenia), there has always been intense speculation

Zinc and epilepsy

Several observations point to a role of endogenous synaptic zinc in the pathophysiology of epilepsy (Frederickson, 1989). First, there is a striking overlap of seizure-prone limbic regions and Timm-positive territories (i.e. hippocampus, amygdala). Second, manipulating brain zinc affects seizure susceptibility. Third, CNS zinc levels are abnormal in seizure-prone animals and seizures can cause substantial modifications of cerebral zinc levels. Nevertheless, whether zinc is a pro- or

Zinc and excitotoxicity

Excitotoxicity is a process during which excessive glutamate release causes over-activation of glutamate receptors, accumulation of intracellular calcium and eventually neuronal death. NMDARs are known to be central in this process, in particular because of their high calcium permeability (Kemp and McKernan, 2002). Excitotoxicity occurs during cerebral ischemia and in neurodegenerative disorders such as Parkinson's and Huntington's diseases. In severe epilepsy, intense seizure activity can also

Manipulating extracellular zinc concentrations using chelators

Many of the past studies on CNS zinc have relied in part or totally on the use of zinc chelators. Zinc chelators are powerful tools but they have limitations. Inappropriate use of certain zinc chelators and/or erroneous interpretation of data obtained with these agents may explain some of the (numerous) discrepancies in the field.

Compounds that chelate zinc avidly (but also other heavy metal ions) are plenty. Some, however, are known to pass cell membranes easily and thus cannot be used to

Conclusion

Several decades after the discovery of brain “chelatable zinc” (Maske, 1955) and its localization in synaptic vesicles (Haug, 1967), the importance of this metal ion in brain function is still disputed. Zinc seems to satisfy several criteria for a neural messenger: it is stored in synaptic vesicles, is possibly released upon depolarization and can act at various membrane targets. The selective association of zinc with glutamate-containing synaptic vesicles suggests that zinc might be a

Acknowledgments

This work was supported by INSERM (P.P.), ANR (P.P. and B.B.) and Région Ile-de-France (A.M.V.).

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Synaptic PlasticityReviewZinc at glutamatergic synapses

Abstract

Section snippets

Localization of brain “chelatable zinc”

Is zinc released during neuronal activity?

Zinc targets at excitatory synapses

Zinc in excitatory synaptic transmission and plasticity

Zinc and epilepsy

Zinc and excitotoxicity

Manipulating extracellular zinc concentrations using chelators

Conclusion

Acknowledgments

Brain Res

Neuroscience

Neuron

Epilepsy Res

Brain Res Mol Brain Res

Neuron

Brain Res

Neuroscience

Int Rev Neurobiol

Brain Res

Brain Res

Brain Res

Neurosci Lett

Neuron

Trends Biochem Sci

Neuron

Neuron

Trends Neurosci

Neuron

Neuroscience

J Nutr

Neurotoxicol Teratol

Brain Res

Neuron

Brain Res

Neuron

Neurosci Lett

Neuron

Brain Res

Biophys J

Exp Neurol

Neuron

Trends Neurosci

Release of endogenous Zn2+ from brain tissue during activity

Nature

Zinc and GABA in developing brain

Nature

Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition

Mol Pharmacol

Zinc and brain injury

Annu Rev Neurosci

Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons

J Neurosci

Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels

J Neurosci

Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene

Proc Natl Acad Sci U S A

Cell type-specific action of seizure-induced intracellular zinc accumulation in the rat hippocampus

J Physiol

Zinc-specific autometallographic in vivo selenium methods: tracing of zinc-enriched (ZEN) terminals, ZEN pathways, and pools of zinc ions in a multitude of other ZEN cells

J Histochem Cytochem

Data for biochemical research

Zinc chelation during non-lesioning overexcitation results in neuronal death in the mouse hippocampus

Neuroscience

The neurobiology of zinc in health and disease

Nat Rev Neurosci

Importance of zinc in the central nervous system: the zinc-containing neurons

J Nutr

Detection and imaging of zinc secretion from pancreatic beta-cells using a new fluorescent zinc indicator

J Am Chem Soc

Synaptic Plasticity
Review
Zinc at glutamatergic synapses

Release of endogenous Zn²⁺ from brain tissue during activity