The development of new imaging tools and transgenic animals has greatly improved our understanding of the physiological and pathophysiological role of Zn2+ in brain functioning.
Neurons have numerous homeostatic systems to maintain extracellular and intracellular Zn2+ concentrations at levels that are non-toxic. Major systems involved in Zn2+ homeostasis include Zn2+ transporters, Zn2+-importing proteins, metallothioneins, lysosomes and mitochondria.
Zn2+ has a major role in controlling synaptic excitability as it can greatly modulate both glutamatergic and GABA (γ-aminobutyric acid)-ergic neurotransmission.
Zn2+ is also potently neurotoxic and has an important role in triggering neuronal death in transient global ischaemia and brain trauma.
Zn2+ is also instrumental in the development of amyloid plaques in Alzheimer's disease. Pharmacological interventions aimed at restoring Zn2+ homeostasis in the brain are yielding promising results in the treatment of patients with Alzheimer's disease.
The past few years have witnessed dramatic progress on all frontiers of zinc neurobiology. The recent development of powerful tools, including zinc-sensitive fluorescent probes, selective chelators and genetically modified animal models, has brought a deeper understanding of the roles of this cation as a crucial intra- and intercellular signalling ion of the CNS, and hence of the neurophysiological importance of zinc-dependent pathways and the injurious effects of zinc dyshomeostasis. The development of some innovative therapeutic strategies is aimed at controlling and preventing the damaging effects of this cation in neurological conditions such as stroke and Alzheimer's disease.
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We are in debt to M. Hershfinkel, A. Vergnano, V. Frazzini, and M.E. Oberschlake for help with the preparation of the manuscript. S.L.S. is supported by funds from the Italian Department of Education (FIRB 2003; PRIN 2006). P.P. is supported by Institut National de la Santé et de la Recherche Médicale (INSERM), France, Agence Nationale de la Recherche (ANR), France, and Fondation pour la Recherche Médicale (FRM; Equipe FRM grant). A.I.B. is supported with funds from the National Health and Medical Research Council of Australia, and The Australian Research Council. Work described in this review was partially supported by ISF grant # 985/05 and GIF grant # 917-119.1/2006 to I.S.
A.I.B. is a paid consultant for and shareholder in Prana Biotechnology Ltd. S.L.S. is a shareholder in Prana Biotechnology Ltd.
A pathological condition observed in newborns that is associated with startle responses (forced eye closure with limb and arm extension, followed by a period of generalized hypertonia) to tactile or acoustic stimuli, truncal hypertonia and episodic apnea. Hyperekplexia can be familial or sporadic. The familial form has been linked to mutations in the α-subunit of the glycine receptor.
- Transient global ischaemia
A particular form of cerebral ischaemia that follows conditions such as cardiac arrest or the near-drowning syndrome. It is characterized by a delayed (7–10 days after the insult) selective form of neuronal death that preferentially targets the hippocampus (in particular its CA1 subregion). TGI seems to be largely modulated by the activation of a subtype of ionotropic glutamate receptor, the AMPARCa–Zn, that lacks the GluR2 subunit and therefore is highly permeable to Ca2+ and Zn2+.
- Unfolded protein response
(UPR). A cellular stress response modulated by the endoplasmic reticulum (ER). Unfolded or misfolded proteins, when accumulated in the ER, activate many chaperones that facilitate proper protein folding in an attempt to restore ER function. When protein folding cannot be restored the UPR has a crucial role in initiating apoptotic pathways that lead to cell death.
- Congophilic angiopathy
The pathological accumulation of β-amyloid in the walls of CNS blood vessels (also known as cerebral amyloid angiopathy). Congophilic derives from the fact that such amyloid deposition can be revealed by Congo red staining.
The form of amyloid-β that is most enriched in amyloid pathology and is most prone to aggregation in vitro. It is also overproduced in some forms of familial AD caused by mutations of APP or presenilins.
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Sensi, S., Paoletti, P., Bush, A. et al. Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 10, 780–791 (2009). https://doi.org/10.1038/nrn2734
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