zinc: the brain's dark horse

Zinc: The Brain’s Dark HorseBYRON K.Y. BITANIHIRWE1

AND MILES G. CUNNINGHAM2,3*1Laboratory of Behavioral Neurobiology, Swiss Federal Institute of Technology, Zurich, Switzerland

2Laboratory for Neural Reconstruction, McLean Hospital, Belmont, Massachusetts3Program in Neuroscience and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

KEY WORDS zinc; zinc homeostasis; central nervous system; gluzinergic neuron;neurological disease

ABSTRACT Zinc is a life-sustaining trace element, serving structural, catalytic,and regulatory roles in cellular biology. It is required for normal mammalian braindevelopment and physiology, such that deficiency or excess of zinc has been shown tocontribute to alterations in behavior, abnormal central nervous system development,and neurological disease. In this light, it is not surprising that zinc ions have nowbeen shown to play a role in the neuromodulation of synaptic transmission as well asin cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutama-tergic or ‘‘gluzinergic’’ neurons and is released in an activity-dependent manner.Because gluzinergic neurons are found almost exclusively in the cerebral cortex andlimbic structures, zinc may be critical for normal cognitive and emotional functioning.Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin.Neuronal injury secondary to in vivo zinc mobilization and release occurs in severalneurological disorders such as Alzheimer’s disease and amyotrophic lateral sclero-sis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integralto normal central nervous system functioning, and in fact its role may be underap-preciated. This article provides an overview of zinc neurobiology and reviews theexperimental evidence that implicates zinc signals in the pathophysiology ofneuropsychiatric diseases. A greater understanding of zinc’s role in the centralnervous system may therefore allow for the development of therapeutic approacheswhere aberrant metal homeostasis is implicated in disease pathogenesis. Synapse63:1029–1049, 2009. VVC 2009 Wiley-Liss, Inc.

INTRODUCTION

Zinc is one of the most abundant nutritionallyessential elements in the human body. It is found in avariety of body tissues, including skin, bone, liver,muscle, and brain. Besides being a structural constit-uent of a great number of proteins, including enzymesbelonging to cellular signaling pathways, zinc is alsoessential for their biological activity (Prasad, 1995;Vallee and Auld, 1993). In particular, zinc plays animportant role in the folding of the DNA-bindingdomains of transcription factors, including the zinc-finger and hormone receptor families (Fredericksonet al., 2000; Macdonald, 2000). Furthermore, zinc hasa variety of effects within the nervous system andthese effects depend on an elaborately regulated andprecisely balanced zinc concentration (Table I) (Colvinet al., 2003, 2008; Frederickson et al., 2005a; Rinkand Gabriel, 2000).

The requirement for zinc is most intimately linkedto its vital role in regulating numerous aspects ofcellular metabolism, including immune (Fraker et al.,

2000; Prasad, 1995, 2008; Rink and Kirchner, 2000),protein (Vallee and Falchuk, 1993), hormone (Hersh-kovitz et al., 1999; MacDonald, 2000; McNall et al.,1995), antioxidant (Bray and Bettger, 1990; Powell,2000; Prasad et al., 2004; Zago and Oteiza, 2001),transcription, and replication functions (Cousins,1998; Vallee and Falchuk, 1993). On the other hand,overabundant levels of zinc can be cytotoxic, inducingapoptosis (Ibs and Rink, 2003; Mackenzie and Oteiza,2007; Telford and Fraker, 1995) and neuronal death(Koh et al., 1996; Sensi and Jeng, 2004). Therefore,intracellular zinc concentration is strictly controlledby zinc importers, exporters, and binding proteinssuch as metallothioneins.

*Correspondence to: Miles G. Cunningham, McLean Hospital, 115 MillStreet, Belmont, MA 02478, USA. E-mail: [email protected]

Received 2 December 2008; Accepted 24 February 2009

DOI 10.1002/syn.20683

Published online in Wiley InterScience (www.interscience.wiley.com).

VVC 2009 WILEY-LISS, INC.

SYNAPSE 63:1029–1049 (2009)

Direct evidence indicates that zinc can act as a neu-romodulator (Colvin et al., 2003; Frederickson andBush, 2001; Kay and Toth, 2008; Nakashima andDyck, 2009; Takeda, 2000; Vogt et al., 2000). Duringsynaptic transmission, zinc can be released into thesurrounding milieu making it available for entry intocells through gated zinc channels on neighboringcells. These zinc releasing neurons also release gluta-mate, and the term ‘‘gluzinergic’’ has therefore beenproposed to describe them (Frederickson, 1989; Fred-erickson and Bush, 2001; Frederickson et al., 2005b).The gluzinergic pathways are found almost exclu-sively in the cerebral cortex and limbic structures(e.g., amygdala, cingulated cortex, hippocampus, andolfactory bulb) of the forebrain (Brown and Dyck,2004; Casanovas-Aguilar et al., 2002; Franco-Ponset al., 2000; Slomianka et al., 1990; Slomianka, 1992).Although the fate of neuronally released zinc is nottotally clear, it seems to modulate the overall excit-ability of the brain through its effect on voltage-gatedcalcium channels (Wang and Quastel, 1990; Weisset al., 1993), glutamate (Smart et al., 1994, 2004), g-aminobutyric acid (GABA) (Smart et al., 1994, 2004),glycine (Baranano et al., 2001; Hirzel et al., 2006;Laube, 2002; Miller et al., 2005), purinergic (Rosatiand Traversa, 1999; Vorobjev et al., 2003; Wildmanet al., 1998, 2002, 2003, Xiong et al., 1999), nicotinic(Hsiao et al., 2001), dopamine (DA) (Schetz and Sib-ley, 1997; Schetz et al., 1999; Swaminath et al., 2002),and serotonin receptors (Gill et al., 1995; Hubbardand Lummis, 2000; Uki and Narahshi, 1996) (Fig. 1).

Within the neuron, zinc may activate major signal-ing pathways including mitogenic, cyclic guanosinemonophosphate (cGMP), cyclic adenosine monophos-phate (cAMP), and phosphoinositide-3 kinase-Akt/PKB pathways (Azriel-Tamir et al., 2004; Barthelet al., 2007; Klein et al., 2002, 2004; Malaiyandiet al., 2005; Min et al., 2007; Watjen et al., 2001). Inparticular, zinc can modulate second messenger sig-

naling molecules important for neuroplasticity, suchas protein kinase C and calcium/calmodulin depend-ent protein kinase (Baba et al., 1991; Lengyel et al.,2000). Furthermore, zinc has recently been shown toinduce transactivation of the receptor tyrosine kinaseB (TrkB) in cornu ammonis 3 (CA3) hippocampal cells(Huang et al., 2008). In addition to zinc’s essentialrole in cellular physiology, several studies in the liter-ature have reported that zinc plays a role in synapticplasticity, a key mechanism for learning and memory(Brown and Dyck, 2002, 2003a, 2005; Huang et al.,2008; Kodirov et al., 2006; Land and Akhtar, 1999;Land et al., 2001, 2002; Li et al., 2001; Nakashimaet al., 2008; Nakashima and Dyck, 2008, 2009; Saitoet al., 2000; Takeda et al., 2009). Therefore, the gluta-mate and zinc-releasing neuronal system appears tocomprise an elaborate network within the corticolim-bic system contributing to both limbic and cortical de-velopment and processing.

In this article, we describe the biology of glutamate-and zinc-releasing neurons (herein labeled gluzinergicneurons) and explain the importance of zinc-regulatedprocesses. We also review the experimental evidencethat implicates zinc signals in the pathophysiology ofneurological diseases.

DISCOVERY OF GLUZINERGIC NEURONS

Zinc was first identified in the brain by Maske whooriginally observed conspicuous bright red bands ofzinc-dithizonate staining within rat hippocampalslices (Maske, 1955). It is now known that in mossyfiber terminals, as well as in other brain regions,vesicular zinc colocalizes in neurons using glutamateas a neurotransmitter (Beaulieu et al., 1992; Frede-rickson, 1989). The concentration of zinc within thesevesicles has been estimated to be as high as millimo-lar levels (Assaf and Chung, 1984; Fredericksonet al., 2000; Howell et al., 1984; Qian and Noebles,

TABLE I. Areas of influence of zinc in the central nervous system

Function influenced by zinc References

Apoptosis (Mackenzie and Oteiza, 2007; Telford and Fraker, 1995; Truong-Tran et al., 2000, 2001, 2002)Audition (Frederickson et al., 1988; Rubio and Juiz, 1998)Free radical management (Bray and Bettger, 1990; Powell, 2000; Prasad et al., 2004; Zago and Oteiza, 2001)Hormone activity (Hershkovitz et al., 1999; MacDonald, 2000; McNall et al., 1995)Immune efficiency (Fraker et al., 2000; Prasad, 1995, 2008; Rink and Kirchner, 2000; Ibs and Rink, 2003)Intracellular signaling (Cousins, 1998; Frederickson et al., 2005a,b; Prasad, 1995; Vallee and Auld, 1993)Learning and memory

(long-term potentiation)(Huang et al., 2008; Kodirov et al., 2006; Lu et al., 2000; Saito et al., 2000; Takeda et al., 2009)

Motor coordination (Jo et al., 2000b; Vincent and Semba, 1989)Neurogenesis (Dvergsten, 1984a; Frederickson et al., 2000)Neuromodulation (Colvin et al., 2003, 2008; Kay and Toth, 2008; Nakashima and Dyck, 2009)Neuronal migration (Dvergsten, 1984b; Frederickson et al., 2000)Nociception (Jo et al., 2000b; Larson and Kitto, 1997, 1999)Olfaction (Alpers, 1984; Jo et al., 2000a; Mackay-Sim and Dreosti, 1989)Protein structural conformation (Coleman, 1992; Vallee and Falchuk, 1993)Regulation of enzyme activity (Coleman, 1992; Vallee and Falchuk, 1993)Synaptic plasticity (Brown and Dyck, 2002, 2005; Huang et al., 2008; Nakashima and Dyck, 2009; Smart et al., 2004)Synaptogenesis (Dvergsten et al., 1983)Vision (Gong et al., 2004; Grahn et al., 2001; Redenti and Chappell, 2005; Ugarte and Osborne, 2001)

1030 B.K.Y. BITANIHIRWE AND M.G. CUNNINGHAM

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2005; Ueno et al., 2002). These long glutamatergicpathways that project into the cerebral cortex as wellas those that project corticopedally to subcortical tar-gets also contain vesicular zinc (Beaulieu et al., 1992;Brown and Dyck, 2004; Casanovas-Aguilar et al.,1995, 1998, 2002; Garrett and Slomianka, 1992;Perez-Clausell and Danscher, 1985). In this regard,gluzinergic neurons contribute almost half of all ofglutamatergic synapses (Sindreu et al., 2003),whereas glutamatergic pathways that originate out-side the cerebral cortex and limbic nuclei contain onlylimited amounts of stainable metals (Danscher et al.,1985; Frederickson et al., 1992).

ANATOMY OF THE GLUZINERGIC CIRCUITRY

Zinc containing somata are mainly restricted tohigher brain regions in the cerebral cortex (includingallocortex) and in the amygdalar nuclei (Christensenand Frederickson, 1998; Perez-Clausell et al., 1989;Slomianka et al., 1990). These gluzinergic neuronsparticipate in a wide variety of intrinsic cortical andamygdaloid pathways, giving rise to widely distrib-

uted zinc-rich terminal fields in the cerebral cortex,amygdala, olfactory bulb, striatum, and limbic struc-tures, such as the septum and the nucleus of the di-agonal and medial hypothalamus (Brown and Dyck,2003b, 2004; Christensen and Frederickson, 1998;Dyck et al., 1993; Howell et al., 1991; Long et al.,1995; Mandava et al., 1993; Perez-Clausell andDanscher, 1986; Perez-Clausell et al., 1989; Valenteet al., 2002).

The major gluzinergic networks within the telen-cephalon form an associational network that recipro-cally interconnects isocortical, allocortical, and limbicsites (Long et al., 1995). The perirhinal cortex is aprominent node in this network (Christensen andFrederickson, 1998; Frederickson and Moncrieff,1994). Gluzinergic neurons in the perirhinal cortexproject widely throughout the neocortex and allocor-tex as well as the septum (Howell et al., 1991; Longet al., 1995; Mandava et al., 1993). In addition, theperirhinal cortex is densely innervated by zinc richfibers, with the entorhinal-perirhinal boundaryalways distinct in zinc histochemistry (Brown andDyck, 2004; Christensen and Frederickson, 1998).

Fig. 1. Zinc trafficking at the gluzinergic synapse. Zinc enterssynaptic vesicles of gluzinergic terminals via the zinc transporter(ZnT-3) and is stored with glutamate. During normal stimulation,zinc is released along with glutamate into the synaptic cleft whereit can then act on postsynaptic channel proteins such as GABAreceptors, NMDA receptors, voltage-gated channels, or a number ofother ion channels to alter their activity, many of which have notbeen well defined; e.g., the unknown channel illustrated on the glialcell membrane (question mark). Metallothioneins (MT) are primary

intracellular zinc-buffering proteins and they regulate the availabil-ity of free zinc in presynaptic terminals and postsynaptic neurons.The metallothionein molecule (inset) consists of two domains, ineach of which zinc is bound in a cluster. In one domain, three zincatoms are bound to nine cysteines (cys), whereas in the otherdomain, four zinc atoms are bound to eleven cysteines. Each zincatom is tetrahedrally coordinated to four thiolate bonds with someof the thiolate ligands sharing the zinc atom.

1031ZINC: THE BRAIN’S DARK HORSE

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The amygdalar complex and the hippocampus(including the subiculum) also constitute major partsof the cerebral gluzinergic network. All amygdalarnuclei are innervated by zinc rich fibers, and most ofthe nuclei also send zinc-containing efferents to bothlocal and remote targets (Brown and Dyck, 2004;Christensen and Frederickson, 1998; Christensen andGeneser, 1995; Howell et al., 1991). Notably, the amyg-dalar nuclei send heavy zinc-containing innervation tothe bed nucleus of the stria terminalis, the lateral

entorhinalcortex, pyriform cortex, striatum, and peria-mygdalar cortices (Brown and Dyck, 2004; Christensenand Frederickson 1998; Howell et al., 1991; Perez-Clausell et al., 1989). By contrast, the hippocampusappears to consist of four sets of gluzinergic neurons:the dentate granule neurons, CA3 pyramidal neurons,CA1 pyramidal neurons, and prosubicular neurons.These neurons are arranged in a serial circuit that ter-minates in part with the subicular pyramidal neuronsthat are apparently zinc-free (Frederickson et al.,1990; Long et al., 1995). Neurons that contain zinc arealso present in other allocortical regions, such as thepyriform cortex, which in turn innervate the amygda-lar complex (Brown and Dyck, 2004; Christensenet al., 1992; Frederickson et al., 1990).

Zinc may be critical to the development, plasticity,and function of the corticolimbic system as indicatedby studies looking at the basolateral amygdaloidinnervation of medial prefrontal cortex, which haveshown that zinc-containing basolateral neurons con-tribute a substantial proportion of medial prefrontalcortex innervation. In a recent study using an auto-metallography technique, up to 35% of basolateralneurons, particularly from the posterior division, pro-jecting to medial prefrontal cortex were found to con-tain zinc (Cunningham et al., 2007) (Fig. 2). Given itsrole in long-term potentiation (Huang et al., 2008;Kodirov et al., 2006; Lu et al., 2000; Nakashimaet al., 2008; Saito et al., 2000; Takeda et al., 2009),the authors suggest that zinc may contribute tosynaptic reorganization that occurs with emotionalexperience and the consolidation of limbic memory.Indeed, the function of basolateral-derived synapticzinc within the medial prefrontal cortex can beconsidered as perhaps an integral component oflimbic-cortical physiology.

ZINC AND CENTRAL NERVOUSSYSTEM FUNCTION

Because gluzinergic neurons are prevalent through-out the limbic system (Slomianka, 1992) and zinc iscapable at physiological concentrations of exertingneuromodulatory effects on receptors thought to beinvolved in learning and memory (Smart et al., 2004;Weiss et al., 1989; Xie and Smart, 1991, 1994), synap-tically released zinc has been considered to play animportant role in memory formation (Lu et al., 2000;Saito et al., 2000; Takeda et al., 2009), which mayinclude emotional memory (Cunningham et al., 2007;Kodirov et al., 2006). In fact, it has been reportedthat zinc is involved in hippocampal mossy fiber long-term potentiation by acting through the TrkB recep-tor (Huang et al., 2008). Moreover, zinc seems to beimportant for neurogenesis, neuronal migration, andsynaptogenesis (Dvergsten et al., 1983, 1984a,b;Frederickson et al., 2000; Sandstead et al., 2000)

Fig. 2. Fluorogold retrograde tracing combined with autometal-lography illustrates that a large percentage of neurons that residewithin the basolateral amygdalar (BLA) nucleus and innervatingthe medial prefrontal cortex (CG1, PL, IL) are gluzinergic. Panel(A) shows a coronal section of a Fluorogold injection into the ratmedial prefrontal cortex. In (B), after an autometallography proce-dure, gluzinergic neurons in the BLA are found labeled with both adense perinuclear reaction product as well as Fluorogold (arrows).This study suggests that these amygdalo-cortical neurons areglutamatergic and thus excitatory, because glutamate and zinc areknown to always coexist, and it implies that zinc is integral to thephysiology and plasticity of this neural relay that is central toemotional circuitry. Cortical layers I–VI in roman numerals; CG1,cingulate cortex area 1; Fmi, forceps minor corpus callosum; IL,infralimbic cortex; PL, prelimbic cortex.


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suggesting that zinc also serves a specialized role fornormal neurophysiological development.

The presence of histochemically reactive zinc in thestriatum (Vincent and Semba, 1989), olfactory bulb (Joet al., 2000a), retinal pigment epithelium (Gong et al.,2004; Grahn et al., 2001; Redenti and Chappell, 2005;Redenti et al., 2007; Ugarte and Osborne, 2001), dorsalcochlear nucleus (Frederickson, 1989; Rubio and Juiz,1998), and spinal cord (Jo et al., 2000b) suggests thatthe neuromodulatory effects of zinc are involved inmotor coordination, olfaction, vision, processing ofauditory stimuli, and nociception, respectively. Con-sistent with this possibility, zinc deficiency induced bya lack of zinc in the diet, by zinc chelation, or by clinicaldisease processes which inhibit zinc absorption and/orutilization are associated with impairment of sensoryperception including loss of taste and smell (Alpers,1994; Mackay-Sim and Dreosti, 1989; Shigihara et al.,1987), pain (Larson and Kitto, 1997, 1999), impairedvision (Age-Related Eye Disease Study, 2001; McClainet al., 1983), and spatial learning (Daumas et al., 2004;Frederickson et al., 1990; Lassalle et al., 2000) as wellas working memory deficits (Halas et al., 1983, 1986).

Zinc has been shown to act as a potent inhibitor ofN-Methyl-D-Aspartate (NMDA) and GABA receptorsas well as glutamate and GABA transporters (Cohen-Kfir et al., 2005; Smart et al., 1994, 2004; Quinta-Fer-reira and Matias, 2004). Therefore following presyn-aptic release, zinc may render forebrain neuronsmore excitable (Forsythe et al., 1988; Lin et al., 2001;Mayer and Vyklicky, 1989), less excitable (Draguhnet al., 1990), or have no net effect (Xie and Smart,1994). However, chelation of endogenous zinc can pro-duce paroxysmal epileptiform brain activity (Mitchelland Barnes, 1993), lowered threshold for seizureinduction (Cole et al., 2000; Dominguez et al., 2003),or potentiate NMDA receptor currents (Kim et al.,2002), which indicates that the main effect of zinc inthe normal brain is to reduce excitability, therebyfunctioning as an endogenous anticonvulsant. Theconverse treatment, on the other hand, intracranialadministration of zinc salts is directly cytolethal andalso proconvulsive (Itoh and Ebadi, 1982; Mortonet al., 1990), therefore suggesting that strict homeo-stasis of zinc is critical for normal brain functioning.

Accumulating evidence also suggests an importantrole for zinc in cognitive function. There have beenreports of a positive relationship between dietaryintake of zinc and normal psychosocial functioning(Bhatnagar and Tenaja, 2001; Bhatnagar and Natch,2004; Black, 1998, 2003a,b; Gardner et al., 2005; Mar-cellini et al., 2006; Sandstead, 2003). Perhaps, rele-vant to the latter connection are the findings suggest-ing that zinc can reduce neurite outgrowth andbranching by inhibiting the binding of nerve growthfactor (NGF) to its receptor, TrkA (Ross et al., 1997).Because synaptogenesis and dendritic branching

serve an essential role in synaptic plasticity in addi-tion to learning and memory processes (Martin et al.,2000; Muller et al., 2000, 2002: Remy and Spruston,2007), zinc might exert profound effects on cognitivefunctioning through such mechanisms. Although thishas not been well studied, recent evidence has impli-cated zinc in mental retardation, synaptic plasticity(i.e., synaptogenesis and dendritic branching), andcognition (Brown and Dyck, 2002, 2003a, 2005;Chechlacz and Gleeson, 2003; Dvergsten et al., 1983,1984a,b; Frederickson et al., 2000; Huang et al., 2008;Kodirov et al., 2006; Land and Akhtar, 1999; Landand Shamalla-Hannah, 2001, 2002; Li et al., 2001;Nakashima et al., 2008; Nakashima and Dyck, 2009;Prasad, 2003; Saito et al., 2000, 2001; Sandsteadet al., 2000; Takeda et al., 2008). Future research is,therefore, needed to clarify the role that zinc mightplay in synaptogenesis, dendritic branching, and howthese processes might relate to NGF-TrkA activationand cognitive processes.

CELLULAR ZINC HOMEOSTASIS

Depending on the intracellular concentration, zinccan regulate either normal or pathological cellularfunctions (Fig. 3). Similar to intracellular calciumhomeostasis, physiological regulation of intracellularzinc levels is the result of a fine balance between ionsequestration, intracellular buffering, and extrusion(Colvin et al., 2003, 2008; Sekler et al., 2007; Takeda,2000, 2001). Zinc sequestration and buffering is largelyregulated by a family of proteins called metallothio-neins, whereas zinc uptake and extrusion is mediatedby the membrane associated zinc transporter family(Eide, 2004; Kagi, 1993; Hidalgo et al., 2001). Further-more, there is now evidence suggesting that intracellu-lar zinc accumulations arise from intracellular storessuch as those associated with mitochondria (Lavoieet al., 2007; Sensi et al., 2002, 2003).

Metallothioneins

Metallothioneins (MTs) are ubiquitous low molecu-lar weight proteins high in cysteine and metal con-tent and devoid of aromatic amino acids. They arepresent in animals, plants, fungi, cyanobacteria, andprokaryotes. Human MTs are encoded by a multigenefamily located on chromosome 16. This multigenefamily consists of 10 functional genes including sevenMT-1 genes (MT-1A, -B, -E, -F, -G, -H, and -X) inaddition to the MT-2A, MT-3, and MT-4 genes (Karinet al., 1984; Palmiter et al., 1992; Quaife et al., 1994;West et al., 1990). The human MTs bind up to sevenzinc atoms and contain 61–68 amino acids from which20 are highly conserved cysteines (Kagi, 1993). Thesecysteine residues are grouped into two domains forzinc binding, resulting in a dumbbell-shaped physicalconformation (Fig. 1, inset) (Arseniev et al., 1988;Robbins and Stout, 1991).


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Distinct MT isoforms have been identified in mam-mals, designated MT-1 through MT-4 (Vasak and Has-ler, 2000). In the central nervous system (CNS), MTsshow a diverse pattern of expression with MT-1 andMT-2 being largely expressed in astrocytes and spinalglia but largely absent in neurons (Acarin et al.,1999; Mocchegiani et al., 2001; Penkowa et al., 1999;Vela et al., 1997) and they have been shown to protectthe CNS from damage induced by interleukin (Giraltet al., 2002), 6-aminonicotinamide (Penkowa et al.,2002), kainic acid (Carrasco et al., 2000), and physicalinjury (Giralt et al., 2000). In contrast, MT-3 appearsto be expressed exclusively in neurons (Palmiteret al., 1992; Uchida, 1994; Yu et al., 2001) andappears to play a significant role in neuronal zinchomeostasis because of its widespread distribution inthe brain and its association with neurons containingsynaptic zinc (Frederickson and Moncrieff, 1994;Masters et al., 1994). However, MT-3 has also beenimplicated in the pathophysiology of neurological die-ases. Various studies have demonstrated that MT-3prevents neuronal sprouting in vitro (Uchida et al.,1991) appears to be downregulated in Alzheimer’s dis-ease (Tsuji et al., 1992; Uchida, 1994; Yu et al., 2001),and in MT-3 knockout mice, the animals are renderedhighly sensitive to kainic acid induced seizures(Erickson et al., 1997).

MT-1 and MT-2 have been the most extensively stud-ied: their expression is regulated at the transcriptionallevel and their promoter regions contain several metal(Hamer, 1986) and glucocorticoid responsive elements(Hager and Palmiter, 1981) as well as elementsinvolved in basal level transcription. Thus, metals,glucocorticoids, cytokines, and reactive oxygen species

converge to induce the expression of both these MTs(Aschner, 1997; Hidalgo et al., 2001). On the otherhand, the MT-3 isoform is not easily induced byexposure to the above agents (Zheng et al., 1995).

The function of MTs is to regulate intracellular zincconcentration and to control detoxification of nones-sential metals (Chan et al., 2002; Moffatt and Deni-zeau, 1997; Vasak, 2005). MTs may therefore serve tosequester zinc and to release it by events that signalits requirement, such as oxidative signaling (Maret,2000; Maret and Vallee, 1998; Jiang et al., 1998;Vasak, 2005). In addition, MT interaction with nitricoxide, which increases during oxidative stress, hasbeen shown to be employed by biological systems torelease zinc (Spahl et al., 2003). In this regard, thenumerous zinc coordination sites of proteins (includingtranscription factors and signaling molecules) providethe opportunity for the cellular MT level to influencekey processes, including gene regulation, cell proli-feration and differentiation, signal transduction, andapoptosis (Davis and Cousins, 2000).

Transporters

Mammalian zinc transporters belong to two genefamilies: (1) the ZnT proteins [solute-linked carrier 30(SLC30)] and (2) the Zip (Zrt- and Irt-like proteins)family [solute-linked carrier 39 (SLC39)]. ZnT and Zipproteins appear to play opposite roles in cellular zinchomeostasis, where ZnT transporters reduce cytosoliczinc bioavailability by facilitating zinc efflux fromcells and promoting accumulation into intracellularvesicles, while Zip transporters function by increasingcytosolic zinc by promoting extracellular and,perhaps, vesicular transport into cytoplasm (Kambe

Fig. 3. Zinc balance must be strictly regulated to maintain homeostasis. Both zinc overload andzinc deficiency are associated with pathologic processes in the central nervous system.


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et al., 2004; Liuzzi and Cousins, 2004; Palmiter andHuang, 2004; Seve et al., 2004). Although relativelylittle is known about the mechanisms of activity andregulation of zinc transporters, the involvement ofsome of these proteins in zinc transport has beenassessed by overexpression studies measuring zincuptake/efflux or zinc accumulation in various systemsincluding mammalian cells, zinc-sensitive yeaststrains, and Xenopus oocytes (Chimienti et al., 2004;Cragg et al., 2002; Huang et al., 2002; Huang andGitschier, 1997; Kambe et al., 2002; Kirschke andHuang, 2003; Palmiter and Findley, 1995; Palmiteret al., 1996a,b).

The ZnT family includes over 100 members, includ-ing many found in prokaryotes (Palmiter and Huang,2004). Most ZnT proteins contain a common struc-ture, consisting of six transmembrane domains and ahistidine-rich cytoplasmic rod (Huang and Gitschier,1997). To date, 10 human SLC30 genes which codefor 10 ZnTs (i.e., ZnT1 to ZnT-10) have been charac-terized (Cousins et al., 2006). Of these, ZnT-1 andZnT-3 are especially interesting, as their brain distri-bution is to a large extent colocalized with zinccontaining synaptic vesicles (Palmiter and Findley,1995, 1996a; Sekler et al., 2002; Tsuda et al., 1997;Valente and Auladell, 2002; Wenzel et al., 1997), andZnT-3 is actually localized on these vesicles (Danscheret al., 2003; Linkous et al., 2008; Palmiter et al.,1996a; Wenzel et al., 1997). Studies in ZnT-3 knock-out mice have demonstrated that ZnT-3 is requiredfor zinc transport into synaptic vesicles (Cole et al.,1999). These animals exhibit undetectable levels ofzinc in their brain. Despite this significant loss, theseanimals exhibit no major phenotype (Cole et al., 1999,2001; Lopantsev et al., 2001). In fact, the only irregu-larity observed in these mice was an increased sus-ceptibility to kainic acid induced seizures (Cole et al.,2000). By contrast, ZnT-1 is responsible for zinc effluxfrom cells and has been suggested to play a role inpreventing zinc toxicity (Palmiter and Findley, 1995;McMahon and Cousins, 1998; Sekler et al., 2002).Therefore, the rapid changes in extracellular zinc andthe numerous pathways for permeation of this ionsuggest an important role for the ZnT proteins inbrain physiology and pathophysiology; however, thenature and physiological roles played by ZnT proteinsin neurons have yet to be elucidated.

The Zip family is typified by an eight-transmem-brane domain structure. A common feature amongZip proteins is a long loop region between transmem-brane domains three and four and a very shortcarboxyl terminus. More than 90 members have beenidentified in various species (Eide, 2004, 2006;Gaither and Eide, 2001). In mammals, 14 SLC39genes which code their respective Zip proteins havebeen characterized (Cousins et al., 2006). MostZip proteins have been observed at the plasma

membrane; however, Zip7 was located at the Golgiapparatus (Huang et al., 2005). The zinc transportmechanism(s) of mammalian Zip proteins have beenpartially elucidated (Eide, 2006; Gaither and Eide,2000, 2001). These studies provide convincing evi-dence that zinc uptake by Zip proteins may bemediated by a facilitated process dependent upon aconcentration gradient to provide the free energy fornet movement of zinc into the cell.

ZINC AND THE REGULATION OF APOPTOSIS

Direct evidence suggests that both zinc overloadand deficiency can lead to an increased susceptibilityof cells to undergo apoptosis (Clegg et al., 2005;Fraker and Telford, 1997; Fraker, 2005; Perry et al.,1997; Sunderman, 1995; Telford and Fraker, 1995;Truong-Tran et al., 2000, 2001, 2002; Zalewski et al.,1993), which can in turn affect critical processes suchas embryogenesis (Jankowski-Hennig et al., 2000)and immune function (Fraker et al., 2000, Fraker,2005). Because physiological levels of zinc in the bodycan be increased in a relatively nontoxic manner, itmay be possible to prevent or reverse the pathologicalprocesses associated with high rates of apoptotic celldeath. This section will therefore review the evidencerelating zinc to apoptosis.

High zinc concentration

High concentrations of zinc can induce apoptosis incortical cell cultures as evidenced by the presence ofDNA fragmentation (Kim et al., 1999a,b). Further-more, it has been shown that high levels of zinc mayresult in programmed cell death in cultured C6 rat gli-oma cells (Watjen et al., 2002) and thymocytes (Frakerand Telford, 1997). Moreover, there are reports indicat-ing that release of intracellular zinc, triggered by for-mation of reactive oxygen species or by nitrosilation,induces proapoptotic molecules (e.g., p38, and activa-tion of potassium channels) leading to cell death (Kimet al., 1999a,b; McLaughlin et al., 2001).

Elevated levels of zinc may also induce cell deaththrough inhibition of energy metabolism (Brown et al.,2000; Sheline et al., 2000). In this respect, a sensitivetarget of zinc toxicity is the mitochondrial respirationchain, with evidence indicating that zinc can dissipatethe mitochondrial membrane potential (Dineley et al.,2003, 2005; Link and von Jagow, 1995; Mills et al.,2002). Chelation of intracellular zinc then, using ahigh affinity zinc chelator such as NNN0N0-tetrakis-(2-pyridil-methyl)ethylenediamine (TPEN) or calciumethylene diamine tetraacetic acid (calcium-EDTA),could interfere with the processes mentioned earlier.However, chelation of intracellular zinc may removezinc from intracellular metalloproteins, resulting inprotein synthesis-dependent, caspase-3 mediatedapoptosis (Truong-Tran et al., 2002).


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Low zinc concentration

Zinc depletion in vitro increases the gene expressionlevel of pro-inflammatory interleukin-1b (Bao et al.,2003), enhances caspase activity (Truong-Tran et al.,2001), and decreases the activity of cytosolic protein ki-nase C (an enzyme linked to caspase-3 processing andactivity) (Chou et al., 2004), all events that may triggerapoptosis. On the contrary, increased levels of zincappear to play an antiapoptotic role with calcium/mag-nesium dependent endonucleases, caspases, Bcl2/Baxratios as well as cytoskeletal components being someof the proposed targets that zinc modulates with a pro-tective outcome (Aiuchi et al., 1998; Chai et al., 1999;Fukamachi et al., 1998; Truong-Tran et al., 2000).Towards this end, chelation with zinc-histide com-plexes (compounds that provide an increased bioavail-ability of zinc) has been shown to protect against oxi-dative insults and to inhibit apoptosis in cultured neu-rons (Williams et al., 2004). Conversely, addition of thezinc-specific chelator TPEN abolishes the inhibition ofapoptosis mediated by zinc (Zalewski et al., 1993).

Zinc may also be involved in triggering apoptosisbecause of its role in the regulation of DNA repair(Kunzmann et al., 2008; Mocchegiani et al., 2000)and by contributing to the DNA binding activity oftranscription factors such as activator protein 1(AP1), nuclear factor jB (NFjB), nuclear factor ofactivated T-cells (NFAT), and poly(ADP-ribose)poly-merase-1 (PARP-1). These transcription factors areexpressed in the brain and are involved in the con-trol of antioxidant response. The elevation of oxidantspecies leads to the activation of the mitogen-acti-vated protein kinase (MAPK)/AP1 (Crossthwaiteet al., 2002), NFjB (Mattson and Moffert, 2006), andNFAT signaling cascades (Mackenzie and Oteiza,2007). Therefore, neuronal apoptosis stemming fromzinc deficiency can be in part due to alterations incell proliferation and survival signals (Clegg et al.,2005), like ERK and AKT (serine/threonine proteinkinases that phosphorylate a number of transcrip-tion factors as well as regulate translation ofmRNA), and the concomitant inactivation of the sur-vival pathways involving NFjB (Mackenzie et al.,2002, 2006), NFAT (Mackenzie and Oteiza, 2007),and PARP-1 (Midorikawa et al., 2006).

ZINC AND NEUROLOGICAL DISEASE

Zinc is implicated directly or indirectly in thepathogenesis of numerous neurological diseasesincluding Alzheimer’s disease, amyotrophic lateralsclerosis, depression, epilepsy, ischemia, and schizo-phrenia. In this section, we provide an overview ofcurrent knowledge about the effect of zinc deficiencyand excess on the brain and neural tissues in the con-text of these disorders.

Alzheimer’s disease

Biochemical studies have shown zinc to be activelyinvolved in the amyloid dysmetabolism associatedwith Alzheimer’s disease (AD) (Bush et al., 1993; Cor-nett et al., 1998; Cuajungco and Lee, 1997; Danscheret al., 1997; Lovell et al., 1998; Multhaup et al., 1994;Sensi et al., 2007). High concentrations of zinc areobserved in the neuritic plaques and cerebrovascularamyloid deposits from both AD patients and AD-prone transgenic mice (Corrigan et al., 1993; Friedlichet al., 2004; Lee et al., 1999; Lovell et al., 1998; Suhet al., 2000; Zhang et al., 2008). The pathological roleof zinc enriched in amyloid plaques might be the pro-motion of amyloid-b protein (Ab) aggregation as ithas been shown that the interactions of Ab with zincand other biometals can lead to its aggregation invitro (Dong et al., 2003).

Oxidative stress due to diminished antioxidantdefenses and/or increased production of reactive oxy-gen species and free radicals may have pathologicalimplications in neurodegenerative disorders, includ-ing AD (Emerit et al., 2004). Indeed, a relationshipexists between the signs of oxidative stress and thecharacteristic Ab accumulation in brain in AD(Hensley et al., 1995; Markesbery, 1997; Multhaupet al., 1998). Ab-peptides display redox activity andproduce hydrogen peroxide mediated by both oxygenand redox active metal ions such as copper and iron.This reaction can be quenched by zinc (Deibel et al.,1996; Meloni et al., 2007, 2008).

Transgenic models of AD have proved vital in shed-ding light on the importance of synaptic zinc in pro-moting amyloid pathology. The Tg2576 mouse modelis one of the best characterized strains of amyloidprecursor protein (APP) transgenic mice having anamyloid plaque burden that is comparable to thatfound in human AD brains. These mice develop nor-mally until approximately 12 months at which pointAb deposits begin to form in cortical and hippocampalareas (Hsiao et al., 1996). This is accompanied byclear signs of inflammation, behavioral deficits, andlearning disabilities (Hsiao et al., 1996). Interestingly,when these animals are crossed with ZnT-3 knockoutmice, which have no synaptic zinc, they show a dra-matic decrease in cerebral plaque formation (Leeet al., 2002a). In line with these observations, chela-tion of zinc in postmortem tissue promotes Ab resolu-bilization suggesting that zinc plays a strong role inAD by promoting amyloid plaque formation in vivo(Cherny et al., 1999, 2001; Lee et al., 2004).

A second mouse model of AD overexpresses mutantforms of human presenelin 1 (PS1), APP, and tauproteins (3xTg-AD). This animal model mimics bothamyloid and tau AD neuropathologies in an age-dependent manner in disease-relevant brain regions(Oddo et al., 2003a,b). The 3xTg-AD mice express


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synaptic and cholinergic deficits (Oddo et al., 2003a,b,2005), the characteristic reactive gliosis inflammatoryprofile (Kitazawa et al., 2005), as well as cognitionimpairment (Billings et al., 2005) and behavioral andpsychological symptoms of dementia-like behaviors(Gimenez-Llort et al., 2007). In this regard, Sensiet al. (2008) have recently demonstrated increasedlevels of intracellular zinc in cortical cultured neuronsfrom 3xTg-AD mice compared to control mice whenexposed to the oxidizing compound 2,20-dithiodipyri-dine (DTDP). These findings suggest a pivotal roleplayed by genetic factors and oxidative stress in thegeneration of intracellular zinc imbalance in AD-related neuronal degeneration. In another studyusing 3xTg-AD mice, sex-dependent alterations in theregulation of vesicular zinc were observed followingvibrissae plucking (a technique often employed forstudying experience dependent plasticity in therodent) (Nakashima et al., 2008). This study revealedan elevated gluzinergic respose in male 3xTg-ADmice compared to male C57Bl/6 mice following vibris-sae plucking. In contrast, the regulation of vesicularzinc between female 3xTg-AD and C57Bl/6 was simi-lar with both groups showing an increase in vesicularzinc following vibrissae removal. Thus, the majoreffect of AD on the experience-dependent regulationof vesicular zinc was a greater gluzinergic reponse inonly males. Because of the strong evidence supportingzinc’s involvement in cortical plasticity (which isimpaired in AD) as well as processes that may giverise to a sex-difference in the incidence and severityof AD (Lee et al., 2002a), the study by Nakashimaet al. (2008) exemplifies how the regulation ofvesicular zinc may be a significant component inthe progression of AD, especially regarding the sex-dependent element.

In yet another model, mutated forms of PS1 (Duffet al., 1996) and APP proteins (APP-PS1) are overex-pressed in mice (Duff et al., 1996; Holcomb et al.,1998). The APP-PS1 mouse model is characterized bya very rapid onset of Ab plaque pathology and depos-its initially start to appear at 3 months of age(Holcomb et al., 1998; Wengenack et al., 2000). It hasrecently been shown that the deposition of plaques inthe APP-PS1 mouse model is associated with anenrichment of zinc (Stoltenberg et al., 2007). Para-doxically, the same study showed that low dietaryzinc in these mice results in a significant increase inplaque volume, despite apparently unaltered zinc iondistribution (Stoltenberg et al., 2007). Postmortemanalysis of zinc levels in AD brain also appear contra-dictory, with the bulk of the literature reportingincreased zinc levels in AD brain (Cornett et al.,1998; Danscher et al., 1997; Deibel et al., 1996; Lovellet al., 1998; Samudralwar et al., 1995; Thompsonet al., 1988). In contrast, other studies have reportedunchanged (Rulon et al., 2000) or decreased levels of

zinc in AD brain (Andrasi et al., 2000; Corrigan et al.,1993; Panayi et al., 2002). On the whole, there seemsto be a connection between zinc and AD, but thereare too many contradictions to clarify the nature ofthe relationship (Cuajungco and Faget, 2003; Huanget al., 2000).

Amyotrophic lateral sclerosis

Current evidence suggests that mutations in theubiquitously expressed free radical scavengingenzyme, copper/zinc superoxide dismutase (SOD1),contribute to familial amyotrophic lateral sclerosis(ALS) (Rosen et al., 1993). SOD1 binds zinc, andmany of the mutant forms of this enzyme associatedwith ALS show altered zinc binding (Smith and Lee,2007; Vonk and Klomp, 2008). Mutant SOD1 has beenshown to produce motor neuron injury by a toxic gainof function and although the exact mechanism ofaction is unclear, several hypotheses exist, includingaberrant free radical handling, abnormal proteinaggregation and increased susceptibility to excitotoxic-ity. In fact, an increased in vivo peroxidase activity inthe Ala4Val and Gly93Ala species has been reported(Roe et al., 2002). Although an increased peroxidaseactivity has also been reported in vitro (Liochev et al.,1997; Singh et al., 1998) in the His48Gln, Ala4Val,and Gly93Ala variants, these observations have notalways been consistent. Incidentally, Ermilova et al.(2005) have observed no significant differences in thedistribution and levels of zinc in spinal cords ofGly93Ala mice and in blood of ALS patients comparedwith nondiseased controls. This study also showedthat zinc deficiency in Gly93Ala mice accelerates dis-ease progression. Interestingly, this progression of dis-ease could be abrogated by zinc supplementation(Ermilova et al., 2005).

Certain ALS mutant SOD1 proteins have beenshown to have a decreased affinity for zinc (Crowet al., 1997; Lyons et al., 2000), and zinc-deficientSOD1 proteins have been postulated to be the toxicspecies in ALS. Notably, these zinc-deficient SOD1proteins exhibit enhanced copper binding and havebeen suggested to confer toxicity by acquiring a per-oxidase activity resulting in generation of peroxyni-trate and neuronal death (Estevez et al., 1999;Mocchegiani et al., 2005; Mulligan et al., 2008;Roberts et al., 2007).

Metallothionein expression is markedly upregulatedin the brain and liver of patients with ALS (SillevisSmitt et al., 1992, 1994). A similar increase of zincmetalloprotein levels is also observed in the spinalcord of patients with ALS and transgenic mutantSOD1 mice, suggesting these molecules to be affectedin ALS (Blaauwgeers et al., 1996; Gong and Elliott,2000; Sillevis Smitt et al., 1992). Indeed, in theGly93Ala mutant SOD1 transgenic model of ALS,deletion of MT-1, MT-2, or MT-3 results in an acceler-


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ated onset of symptoms and a shorter survival time(Nagano et al., 2001; Puttaparthi et al., 2002). Theseobservations are generally consistent with MTs serv-ing a protective function by binding zinc, and thuspreventing its increase to toxic levels. In summary,impaired SOD1 function and MT-1/-2 and MT-3 induc-tion, in combination with previously described apopto-sis product alterations in mice, suggest a multifacto-rial pathway linking zinc dyshomeostasis to the selec-tive damage observed in ALS.

Depression

Mounting evidence suggests a link between zincdeficiency and depression. For example, clinical datahave demonstrated a lower serum zinc concentrationin patients with depression (Maes et al., 1994, 1997;McLoughlin and Hodge 1990; Nowak et al., 2005).One study, in particular, showed that serum zinc lev-els were significantly lower in severely depressed sub-jects than in normal controls, whereas less severelydepressed subjects showed intermediate values (Maeset al., 1994). Although low levels of zinc have beentied to major depressive disorder, antidepressant ther-apy for this condition by contrast causes an elevationin zinc levels (Nowak and Schlegel-Zawadska, 1999;Nowak et al., 2003). In line with these observations,various studies have shown zinc to exhibit antidepres-sant-like activity in some models (olfactory bul-bectomy, chronic mild stress, chronic unpredic-table stress) of depression (Cieslik et al., 2007;Kroczka et al., 2000, 2001; Nowak et al., 2003, 2005;Rosa et al., 2003; Sowa-Kucma et al., 2008; Tassa-behji et al., 2008). Furthermore, there is evidencedemonstrating that chronic treatment with electro-convulsive shock induces hippocampal mossy fibersprouting (reflecting synaptic zinc level), indicatingan increase in synaptic zinc concentration in thehippocampus following such therapy (Gombos et al.,1999; Lamont et al., 2001; Vaidya et al., 1999).

Although the mechanism of zinc antidepressantactivity is not well understood, several reports sug-gest that clinically effective antidepressants (affectingmonoamine transmitter reuptake or metabolism) mayinhibit the function of the NMDA receptor (Dumanet al., 1997; Skolnick et al., 2001). Zinc is an antago-nist of the NMDA receptor complex (Harrison andGibbsons 1994), so one potential mechanism of theantidepressant activity of zinc might be related to itsdirect antagonism of this receptor. A second mecha-nism may be associated with zinc’s antagonistic actionon group 1 metabotropic glutamate receptors (Zirpeland Parks, 2001) or potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)receptors (Rassendren et al., 1990) which may attenu-ate NMDA receptor function (Skolnick et al., 2001).Another possible antidepressant mechanism throughwhich zinc may exert its effect is by direct inhibition

of glycogen synthase-3b (GSK-3b) activity (Ilouzet al., 2002). This enzyme is proposed to be a targetfor treatment of mood disorders (Gould and Manji,2005; O’Brien et al., 2004; Quiroz et al., 2004). Stillanother potential mechanism may be related to theneurogenic hypothesis of depression (Mayberg, 2007).Loss of hippocampal neurons is found in somedepressed individuals and correlates with impairedmemory and dysthymic mood (Drevets et al., 2008).One of the neurotrophins responsible for neurogenesisis the brain-derived neurotrophic factor (BDNF). Sev-eral reports suggest that alteration in BDNF geneexpression plays a key role in the pathophysiologyand therapy of depression. Brain levels (hippocampaland/or cortical) as well as serum levels of BDNF arereduced in patients with depression, whereas antide-pressant treatment increases this neurotrophic factor(Castren, 2004; Chen et al., 2001; Karege et al., 2005;Sowa-Kucma et al., 2008). Furthermore, BDNF infu-sions into the midbrain (Siuciak et al., 1997) and hip-pocampus (Shirayama et al., 2002) produce antide-pressant effects in rodents. Towards this end, chronictreatment with zinc increases level of BDNF mRNAin the rat cerebral cortex and hippocampus (Nowaket al., 2004; Sowa-Kucma et al., 2008). These observa-tions indicate that zinc increases cortical/hippocampalBDNF gene expression, which is the effect shared bymost clinically effective antidepressants.

Epilepsy

Zinc has been reported to act either as an anticon-vulsant when homeostasis is maintained (Williamsonand Spencer 1995) or as a proconvulsant (Pei et al.,1993) with disturbed homeostasis, perhaps playing arole in the etiology and manifestation of epileptic seiz-ures (Sterman et al., 1988). The importance of synap-tic zinc in contributing to seizure activity has beenclearly supported by animal models of epilepsy(Foresti et al., 2008; Flynn et al., 2007; Fredericksonet al., 1988; Frederickson, 1989; Sloviter, 1985; Suhet al., 2001; Takeda et al., 2003) including the epi-lepsy-like (EL) mouse. Seizures in EL mice commencewith the onset of puberty, originate in or near theparietal lobe, and then spread to the hippocampusand to other brain regions (Ishida et al., 1993; Suzukiet al., 1991; Todorova et al., 1999; Uchibori et al.,2002). The observation that zinc concentration issignificantly lower in the hippocampal dentate area ofEL mice as compared to that of control mice (Fuka-hori et al., 1988) suggests that a decrease of hippo-campal zinc may be involved in the pathophysiologyof convulsive seizures in the EL mice. In these mice,zinc loading reduces seizure susceptibility, while sus-ceptibility is increased by dietary zinc deficiency(Fukahori and Itoh, 1990). Furthermore, ZnT-3knockout and chelation of intracellular zinc have con-


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sistently been found to enhance seizure susceptibility(Blasco-Ibanez et al., 2004; Cole et al., 2000; Mitchelland Barnes, 1993; Takeda et al., 2003). Interestingly,zinc has been found to be depleted in the brains ofEL mice during the induction of seizures (Takedaet al., 1999). Kainic acid induced seizures in EL micetrigger a substantial, but tissue specific loss of zincfrom the brain. In particular, a reduction of zincoccurs in the hippocampus and cerebral cortex wherethere is abundance of gluzinergic neuron terminalsbut not in the cerebellum (Frederickson et al., 1988;Sloviter, 1985; Takeda et al., 2003).

Various studies have shown alterations of struc-tural and receptor distribution in the hippocampus ofpatients with temporal lobe epilepsy and animal mod-els of this condition (Dudek, 2001; Sperk, 2007).These studies suggest an enhanced function of excita-tory synapses selectively using NMDA receptors inafferents of the dentate granule cells in hippocampalslices isolated from kindled animals (Kohr and Mody,1994). Furthermore, it has been shown that the subu-nit composition of GABAA receptors (GABAR) on den-tate granule cells may be altered resulting in a reduc-tion of inhibitory synaptic transmission (Goodkinet al., 2008; Nishimura et al., 2005; Porter et al.,2005; Zhang et al., 2007). Zinc sensitivity is deter-mined to a significant extent by the nature of thea1 subunits contained within a given GABAR(Macdonald and Kapur, 1999; Macdonald and Olsen,1994). GABARs containing a1 and g2 subunits tendto exhibit low zinc sensitivity (Fisher, 2002; Whiteand Gurley, 1995). By contrast, low levels of a1 asso-ciated with g2-containing GABARs result in high zincsensitivity (Burgard et al., 1996; Fisher and Macdon-ald, 1998; White and Gurley, 1995), as is seen in den-tate granule cells in epileptic brain. In addition to thepossible effects of altered subunits of the GABAR,there is evidence indicating that mossy fibers termi-nals undergo synaptic reorganization in the brains ofboth humans and animal models of epileptogenesis.Targets for these sprouted terminals appear to beboth dentate granule cells and inhibitory interneur-ons (Franck et al., 1995; Okazaki et al., 1995). Basedon these observations, it has been proposed thatintense mossy fiber activity (i.e., seizures) results inthe release of large amounts of glutamate and zinc ina short period of time (Coulter, 2000). The releasedzinc diffuses and blocks the new GABARs (i.e., con-taining reduced levels of a1 and g2 subunits) generat-ing a decreased inhibition that contributes to the gen-eration and propagation of seizures in the dentategyrus (Buhl et al., 1996; Hamed and Abdellah, 2004).

Ischemia

Only recently has it been realized that ionic zincmay play a role in the ischemic degenerative events

that follow cerebral stroke (Choi, 1996; Galasso andDyck, 2007; Koh et al., 1996; Sensi et al., 2007;Tønder et al., 1990). In particular, it appears that thehippocampal neurons in the CA1 subregion seem tobe selectively affected in this condition (Pulsinelliet al., 1982). One factor that seems to play a criticalrole in the high vulnerability of these neurons is theirdendritic expression of calcium-permeable AMPA/kai-nate receptor gated (calcium A/K) channels (Bennettet al., 1996; Pellegrini-Giampietro et al., 1997). Thereis now evidence suggesting an ischemia-mediated reg-ulation of the subunit composition of calcium A/Kchannels (Bennett et al., 1996). Accordingly, ischemiaselectively decreases the expression of the AMPAreceptor GluR2 subunit which in turn allows for toxiccalcium as well as zinc to more readily enter CA1pyramidal neurons (Calderone et al., 2003; 2004;Gorter et al., 1997; Opitz et al., 2000; Pellegrini-Giampietro et al., 1997; Sensi and Jeng, 2004).

Pharmacological inhibition of calcium A/K channelshas been found to be highly neuroprotective againstCA1 pyramidal neuronal loss in both in vitro and invivo models of ischemia (Noh et al., 2005; Yin et al.,2002), indicating the role of zinc influx mediated bythese channels in the pathogenesis of ischemia. Fur-thermore, administration of calcium-EDTA, a zinc-selective membrane-impermeable chelator, preventszinc-induced death of cultured cortical neurons (Kohet al., 1996), blocks the accumulation of zinc, reducesinfarct volume (Lee et al., 2002b), and has beenshown to protect hippocampal neurons after transientglobal ischemia (Calderone et al., 2004). Notably, Cal-derone et al. (2004) have demonstrated that earlyapplication of calcium-EDTA can significantly attenu-ate the ischemia induced downregulation of bothGluR2 mRNA and protein expression in the CA1 hip-pocampal subfield, suggesting a role for zinc in signal-ing an increase in calcium A/K channels. In the samestudy, late application of chelator, after calcium A/Kchannels numbers had already risen, was shown toattenuate the late rise in intracellular zinc associatedwith injury, suggesting that calcium A/K channel de-pendent intracellular zinc accumulation contributes tothe delayed injury. Incidentally, Kitamura et al. (2006)have recently shown in a rat transient middle cerebralartery occlusion (MCAO) model of ischemia that a lowconcentration of zinc induced by calcium-EDTA pro-tects against glutamate-induced neuronal death byblocking calcium influx, whereas a high concentrationof zinc exerts its own toxicity independent of calciuminflux. These findings indicate that zinc may exhibitbiphasic effects depending on its concentration.

Recent studies in ischemia suggest that increasedzinc concentration triggered by this disease mightresult from a mitochondrial dysfunction (Bonanni et al.,2006; Sensi et al., 1999, 2000, 2003). Support for such amechanism comes from Frederickson et al. (2006) who


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used micro-dialysis to examine extracellular zinc levelsduring global ischemia and reperfusion. This studyshowed that zinc and glutamate release at ischemiaonset was simultaneous. However, the reperfusion-induced zinc release was longer-lasting, in both inten-sity and duration than the initial ischemic-induced zincrelease. Because zinc release was unaccompanied byglutamate release following reperfusion, it is suggestedthat the reperfusion-induced zinc release represents arelease of zinc from cytoplasmic stores, such as metallo-thioneins (Erickson et al., 1997; Maret, 1995) or mito-chondria (Sensi et al., 1999, 2000, 2003).

Further support implicating mitochondrial dysfunc-tion in ischemia comes from a rat model of global ische-mia that shows alterations in mitochondrial morphol-ogy, mitochondrial zinc elevation, and activation oflarge, multiconductance channels (Bonanni et al.,2006). This channel activity is associated with a power-ful apoptotic signaling mechanism that promotes theproteolytic cleavage of Bcl-xl and which in turn gener-ates the proapoptotic N-terminal cleavage fragment ofBcl-xl (Bonanni et al., 2006, Miyawaki et al., 2008).Zinc chelation with calcium-EDTA prior to ischemiaprevents large conductance channel activity but alsothe morphological alterations. Furthermore, adminis-tration of the membrane-permeable zinc chelatorTPEN has proven effective in inhibiting mitochondrialchannel activity (Bonanni et al., 2006). The aforemen-tioned studies demonstrate that elevated intracellularzinc levels during ischemia serve as a critical mediatorof neuronal death, and zinc inhibition achieved byeither an early or late chelation paradigm may beeffective in preventing zinc neurotoxicity.

Schizophrenia

Schizophrenia is broadly believed to be a neurode-velopmental disorder in which GABA cell dysfunctionin the hippocampal, prefrontal, and anterior cingulatecortices plays an important role (Benes, 2000, Harri-son, 2004; Harrison and Weinberger, 2005; Lewis andGonzales-Burgos, 2006; Lewis and Hashimoto, 2007).A plausible mechanism for GABA cell dysfunction inschizophrenia within amygdalar terminal fields isthat abnormally increased amygdalar activity mayproduce an environment of increased glutamatergictransmission and possibly even oxidative stress (Coyleand Puttfarcken 1993). Therefore excitotoxicity,presumably from the massive (putatively glutamater-gic) innervation from the basolateral nucleus, hasbeen speculated as a potential mechanism for neuro-nal degeneration in the anterior cingulate cortex. Inschizophrenic patients, this region may receive supra-numary glutaminergic vertical processes (Beneset al., 1992), possibly sprouting from an over-stimu-lated amygdala. Consistent with this hypothesis,recent findings from our laboratory suggest that a

significant proportion of basolateral-derived innerva-tion may be in part modulated by zinc, and hencesubject to zinc neurotoxicity during pathologicalprocesses (Cunningham et al., 2007). Incidentally,zinc-associated cytotoxicity has been speculated as amechanism for hippocampal neuronal depletion as aresult of stress (Frederickson et al., 2000). Therefore,the presence of zinc in the basolateral amygaloidterminals may play a crucial modulatory effect viaexcitatory glutamate receptors and calcium A/Kchannels of cingulate cortex GABAergic interneuronsleading to the GABAergic neuronal cell loss found inschizophrenia and experimental excitotoxic modelsof this disease (Benes et al., 1991; Benes, 1995; Lip-ska, 2004; Lipska and Weinberger, 2000; Woo et al.,2004, 2008).

One of the most consistent findings in postmortemstudies of schizophrenia is reduced glutamic aciddecarboxylase (GAD67) expression (Akbarian et al.,1995; Benes et al., 2007; Volk et al., 2000). GADexists in two isoforms (termed GAD67 or GAD1, andGAD65 or GAD2, respectively) that function to pro-duce the inhibitory neurotransmitter GABA from glu-tamate. The activity of GAD has been shown to bemodulated by zinc (Ebadi et al., 1990). Perhaps rele-vant to the latter relationship is that the reducedactivity of GAD in schizophrenia could be associatedwith increased level of neuronal excitation, viaNMDA receptor and calcium A/K channels, whichresults in prolonged intracellular calcium and possi-bly zinc elevation resulting in excitotoxic damage(Carriedo et al., 1998; Lu et al., 1996; Monnerie andLe Roux, 2007). In this regard, electrophysiologicaland histological studies indicate that many GABAer-gic forebrain neurons express large numbers ofcalcium A/K channels, which are highly permeable tozinc ions, (Bochet et al., 1994; Jia et al., 2002; McBainand Dingledine, 1993; Weiss and Sensi, 2000) andsuggest that GABAergic neurons may be the primarypopulation of central neurons expressing large num-bers of these channels. Thus, calcium A/K channelsmay serve as critical routes for trans-synaptic zincsignaling in GABAergic neurons, a mechanism whichhas been suggested to contribute to neuronal death(Weiss and Sensi, 2000) but which may also contrib-ute to the impaired GAD expression observed inschizophrenia.

CONCLUSION

The present review, while summarizing andhighlighting the nature of zinc’s role in the centralnervous system, also proposes a role of zinc in thefunction and plasticity of emotional networks. Thus, asthe synaptic organization of the somatosensory systemis continuously modified by sensory experience, so alsomay be the synaptic organization of the corticolimbic


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system by emotional experience. This would place zincin a vital role for facilitating experience-dependentchanges that occur during development and ‘‘moment-to-moment’’ adaptation in emotional cognition as wellas in the consolidation of limbic memory (Cunninghamet al., 2007; Kodirov et al., 2006).

It is equally clear that zinc homeostasis in thebrain is integral for normal brain function. Altera-tions in zinc levels can have devastating results withzinc becoming a pathogenic agent that mediates neu-ronal death in neurological conditions such as Alzhei-mer’s disease, amyotrophic lateral sclerosis, andischemia. In this regard, studies have focused on thetreatment of patients with metal chelating drugs(Bush, 2000; Doraiswamy and Finefrock, 2004; Gaetaand Hider, 2005). However, caution is warrantedbecause more knowledge of zinc homeostasis isrequired before such therapeutic approaches can bethoughtfully undertaken or interpreted. Providedwith this knowledge, therapies based on manipulatingzinc signals by preventing release, blocking channels,altering transport, and buffering zinc’s concentrationin target tissues are all likely to have increasinglyimportant roles in treating diverse neurologic andneuropsychiatric diseases.

ACKNOWLEDGMENTS

We wish to acknowledge Heather Ames for her con-tributions in understanding the role of zinc withinamygdalo-cortical circuitry. In addition, we are grate-ful to Lauren Brown for helping with the preparationof the diagrams and to Dr. Gabriele Meloni, Dr. Ben-jamin Yee, and Andrei Karotki for critically readingthrough the manuscript.

REFERENCES

Acarin L, Gonzalez B, Hidalgo J, Castro AJ, Castellano B. 1999. Pri-mary cortical glial reaction versus secondary thalamic glialresponse in the excitotoxically injured young brain: Astroglialresponse and metallothionein expression. Neuroscience 92:827–839.

Age-Related Eye Disease Study Research Group. 2001. A random-ized, placebo-controlled, clinical trial of high dose supplementa-tion with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No.8. Arch Opthalmol 119:1417–1436.

Aiuchi T, Mihara S, Nakaya M, Masuda Y, Nakajo S, Nakaya K. 1998.Zinc ions prevent processing of caspase-3 during apoptosis inducedby geranylgeraniol in HL-60 cells. J Biochem 124:300–303.

Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, BunneyWE Jr, Jones EG. 1995. Gene expression for glutamic acid decar-boxylase is reduced without loss of neurons in prefrontal cortex ofschizophrenics. Arch Gen Psychiatry 52:258–266.

Alpers DH. 1994. Zinc and deficiencies of taste and smell. JAMA272:1233–1234.

Andrasi E, Farkas E, Gawlik D, Rosick U, Bratter P. 2000. Brainiron and zinc contents of german patients with alzheimer disease.J Alzheimers Dis 2:17–26.

Arseniev A, Schultze P, Worgotter E, Braun W, Wagner G, Vasak M,Kagi JH, Wuthrich K. 1988. Three-dimensional structure of rabbitliver [Cd7]metallothionein-2a in aqueous solution determined bynuclear magnetic resonance. J Mol Biol 201:637–657.

Aschner M. 1997. Astrocyte metallothioneins (MTs) and their neuro-protective role. Ann N Y Acad Sci 825:334–347.

Assaf SY, Chung SH. 1984. Release of endogenous Zn21 from braintissue during activity. Nature 308:734–736.

Azriel-Tamir H, Sharir H, Schwartz B, Hershfinkel M. 2004. Extra-cellular zinc triggers ERK-dependent activation of Na+/H+exchange in colonocytes mediated by the zinc-sensing receptor.J Biol Chem 279:51804–51816.

Baba A, Etoh S, Iwata H. 1991. Inhibition of NMDA-induced proteinkinase C translocation by a Zn2+ chelator: implication of intracel-lular Zn2+. Brain Res 557:103–108.

Bao B, Prasad AS, Beck FW, Godmere M. 2003. Zinc modulatesmRNA levels of cytokines. Am J Physiol Endocrinol Metab285:E1095–E1102.

Barthel A, Ostrakhovitch EA, Walter PL, Kampkotter A, Klotz LO.2007. Stimulation of phosphoinositide 3-kinase/Akt signaling bycopper and zinc ions: mechanisms and consequences. Arch Bio-chem Biophys 463:175–182.

Baranano DE, Ferris CD, Snyder SH. 2001. Atypical neural messen-gers. Trends Neurosci 24:99–106.

Beaulieu C, Dyck R, Cynader M. 1992. Enrichment of glutamate inzinc-containing terminals of the cat visual cortex. Neuroreport3:861–864.

Benes FM. 1995. Altered glutamatergic and GABAergic mechanismsin the cingulate cortex of the schizophrenic brain. Arch Gen Psy-chiatry 52:1015–1018.

Benes FM. 2000. Emerging principles of altered neural circuitry inschizophrenia. Brain Res Brain Res Rev 31:251–269.

Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL.1991. Deficits in small interneurons in prefrontal and cingulatecortices of schizophrenic and schizoaffective patients. Arch GenPsychiatry 48:996–1001.

Benes FM, Sorensen I, Vincent SL, Bird ED, Sathi M. 1992.Increased density of glutamate-immunoreactive vertical processesin superficial laminae in cingulate cortex of schizophrenic brain.Cereb Cortex 2:503–512.

Benes FM, Lim B,Matzilevich D,Walsh JP, Subburaju S, MinnsM. 2007.Regulation of the GABA cell phenotype in hippocampus of schiyo-phrenics and bipolars. Proc Natl Acad Sci USA 104:10164–10169.

Bennett MV, Pellegrini-Giampietro DE, Gorter JA, Aronica E,Connor JA, Zukin RS. 1996. The GluR2 hypothesis: Ca(11)-per-meable AMPA receptors in delayed neurodegeneration. ColdSpring Harb Symp Quant Biol 61:373–384.

Bhatnagar S, Taneja S. 2001. Zinc and cognitive development. Br JNutr 85(Suppl 2):S139–S145.

Bhatnagar S, Natchu UC. 2004. Zinc in child health and disease.Indian J Pediatr 71:991–995.

Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. 2005.Intraneuronal Abeta causes the onset of early Alzheimer’sdisease-related cognitive deficits in transgenic mice. Neuron45:675–688.

Blaauwgeers HG, Anwar ChandM, van den Berg FM, Vianney de JongJM, Troost D. 1996. Expression of different metallothionein messen-ger ribonucleic acids in motor cortex, spinal cord and liver frompatients with amyotrophic lateral sclerosis. J Neurol Sci 142:39–44.

Black MM. 1998. Zinc deficiency and child development. Am J ClinNutr 68(2 Suppl):464S–469S.

Black MM. 2003a. The evidence linking zinc deficiency with children’scognitive andmotor functioning. J Nutr 133(5 Suppl 1): 1473S–1476S.

Black MM. 2003b. Micronutrient deficiencies and cognitive function-ing. J Nutr 133(11 Suppl 2):3927S–3931S.

Blasco-Ibanez JM, Poza-Aznar J, Crespo C, Marques-Marı AI,Gracia-Llanes FJ, Martınez-Guijarro FJ. 2004. Chelation of syn-aptic zinc induces overexcitation in the hilar mossy cells of therat hippocampus. Neurosci Lett 355:101–104.

Bochet P, Audinat E, Lambolez B, Crepel F, Rossier J, Iino M,Tsuzuki K, Ozawa S. 1994. Subunit composition at the single-celllevel explains functional properties of a glutamate-gated channel.Neuron 12:383–388.

Bonanni L, Chachar M, Jover-Mengual T, Li H, Jones A, Yokota H,Ofengeim D, Flannery RJ, Miyawaki T, Cho CH, Polster BM,Pypaert M, Hardwick JM, Sensi SL, Zukin RS, Jonas EA. 2006.Zinc-dependent multi-conductance channel activity in mitochon-dria isolated from ischemic brain. J Neurosci 26:6851–6862.

Bray TM, Bettger WJ. 1990. The physiological role of zinc as anantioxidant. Free Radic Biol Med 8:281–291.

Brown CE, Dyck RH. 2002. Rapid, experience-dependent changes inlevels of synaptic zinc in primary somatosensory cortex of theadult mouse. J Neurosci 22:2617–2625.

Brown CE, Dyck RH. 2003a. Experience-dependent regulation ofsynaptic zinc is impaired in the cortex of aged mice. Neuroscience119:795–801.

Brown CE, Dyck RH. 2003b. An improved method for visualizing thecell bodies of zincergic neurons. J Neurosci Methods 129:41–47.


Synapse

Brown CE, Dyck RH. 2004. Distribution of zincergic neurons in themouse forebrain. J Comp Neurol 479:156–167.

Brown CE, Dyck RH. 2005. Modulation of synaptic zinc in barrelcortex by whisker stimulation. Neuroscience 134:355–359.

Brown AM, Kristal BS, Effron MS, Shestopalov AI, Ullucci PA,Sheu KF, Blass JP, Cooper AJ. 2000. Zn21 inhibits alpha-ketoglu-tarate-stimulated mitochondrial respiration and the isolatedalpha-ketoglutarate dehydrogenase complex. J Biol Chem275:13441–13447.

Buhl EH, Otis TS, Mody I. 1996. Zinc-induced collapse of aug-mented inhibition by GABA in a temporal lobe epilepsy model.Science 271:369–373.

Burgard EC, Tietz EI, Neelands TR, Macdonald RL. 1996. Propertiesof recombinant gamma-aminobutyric acid A receptor isoforms con-taining the alpha 5 subunit subtype. Mol Pharmacol 50:119–127.

Bush AI. 2000. Metals and neuroscience. Curr Opin Chem Biol4:184–191.

Bush AI, Multhaup G, Moir RD, Williamson TG, Small DH, Rumble B,Pollwein P, Beyreuther K, Masters CL. 1993. A novel zinc(II) bindingsite modulates the function of the beta A4 amyloid protein precursorof Alzheimer’s disease. J Biol Chem 268:16109–16112.

Calderone A, Jover T, Noh KM, Tanaka H, Yokota H, Lin Y, GroomsSY, Regis R, Bennett MV, Zukin RS. 2003. Ischemic insults dere-press the gene silencer REST in neurons destined to die. J Neuro-sci 23:2112–2121.

Calderone A, Jover T, Mashiko T, Noh KM, Tanaka H, Bennett MV,Zukin RS. 2004. Late calcium EDTA rescues hippocampalCA1 neurons from global ischemia-induced death. J Neurosci24:9903–9913.

Carrasco J, Penkowa M, Hadberg H, Molinero A, Hidalgo J. 2000.Enhanced seizures and hippocampal neurodegeneration followingkainic acid-induced seizures in metallothionein-I 1 II-deficientmice. Eur J Neurosci 12:2311–2322.

Carriedo SG, Yin HZ, Sensi SL, Weiss JH. 1998. Rapid Ca21 entrythrough Ca21-permeable AMPA/Kainate channels triggersmarked intracellular Ca21 rises and consequent oxygen radicalproduction. J Neurosci 18:7727–7738.

Casanovas-Aguilar C, Christensen MK, Reblet C, Martınez-GarcıaF, Perez-Clausell J, Bueno-Lopez JL. 1995. Callosal neurones giverise to zinc-rich boutons in the rat visual cortex. Neuroreport6:497–500.

Casanovas-Aguilar C, Reblet C, Perez-Clausell J, Bueno-Lopez JL.1998. Zinc-rich afferents to the rat neocortex: Projections to thevisual cortex traced with intracerebral selenite injections. J ChemNeuroanat 15:97–109.

Casanovas-Aguilar C, Miro-Bernie N, Perez-Clausell J. 2002. Zinc-rich neurones in the rat visual cortex give rise to two laminar seg-regated systems of connections. Neuroscience 110:445–458.

Castren E. 2004. Neurotrophins as mediators of drug effects onmood, addiction, and neuroprotection. Mol Neurobiol 29:289–302.

Chai F, Truong-Tran AQ, Ho LH, Zalewski PD. 1999. Regulation ofcaspase activation and apoptosis by cellular zinc fluxes and zincdeprivation: A review. Immunol Cell Biol 77:272–278.

Chan MK, Othman R, Zubir D, Salmijah S. 2002. Induction of aputative metallothionein gene in the blood cockle. Anadaragranosa, exposed to cadmium. Comp Biochem. Physiol ToxicolPharmacol 131:123–132.

Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. 2001.Increased hippocampal BDNF immunoreactivity in subjectstreated with antidepressant medication. Biol Psychiatry 50:260–265.

Chechlacz M, Gleeson JG. 2003. Is mental retardation a defect ofsynapse structure and function? Pediatr Neurol 29:11–17.

Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS,Beyreuther K, Tanzi RE, Masters CL, Bush AI. 1999. Aqueousdissolution of Alzheimer’s disease Abeta amyloid deposits by bio-metal depletion. J Biol Chem 274:23223–23228.

Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLeanCA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Gold-stein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE,Masters CL, Bush AI. 2001. Treatment with a copper-zinc chela-tor markedly and rapidly inhibits beta-amyloid accumulation inAlzheimer’s disease transgenic mice. Neuron 30:665–676.

Chimienti F, Devergnas S, Favier A, Seve M. 2004. Identificationand cloning of a beta-cell-specific zinc transporter. ZnT-8, localizedinto insulin secretory granules. Diabetes 53:2330–2337.

Choi DW. 1996. Zinc neurotoxicity may contribute to selective neu-ronal death following transient global cerebral ischemia. ColdSpring Harb Symp Quant Biol 61:385–387.

Chou SS, Clegg MS, Momma TY, Niles BJ, Duffy JY, Daston GP, KeenCL. 2004. Alterations in protein kinase C activity and processingduring zinc-deficiency-induced cell death. Biochem J 383:63–71.

Christensen MK, Geneser FA. 1995. Distribution of neurons of ori-gin of zinc-containing projections in the amygdala of the rat. AnatEmbryol 191:227–237.

Christensen MK, Frederickson CJ. 1998. Zinc-containing afferentprojections to the rat corticomedial amygdaloid complex: A retro-grade tracing study. J Comp Neurol 400:375–390.

Christensen MK, Frederickson CJ, Danscher G. 1992. Retrogradetracing of zinc-containing neurons by selenide ions: A survey ofseven selenium compounds. J Histochem Cytochem 40:575–579.

Cieslik K, Klenk-Majewska B, Danilczuk Z, Wrobel A, Lupina T,Ossowska G. 2007. Influence of zinc supplementation on imipr-amine effect in a chronic unpredictable stress (CUS) model inrats. Pharmacol Rep 59:46–52.

Clegg MS, Hanna LA, Niles BJ, Momma TY, Keen CL. 2005. Zincdeficiency-induced cell death. Life 57:661–669.

Cohen-Kfir E, Lee W, Eskandari S, Nelson N. 2005. Zinc inhibitionof gamma-aminobutyric acid transporter 4 (GAT4) reveals a linkbetween excitatory and inhibitory neurotransmission. Proc NatlAcad Sci USA 102:6154–6159.

Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD.1999. Elimination of zinc from synaptic vesicles in the intactmouse brain by disruption of the ZnT3 gene. Proc Natl Acad SciUSA 96:1716–1721.

Cole TB, Robbins CA, Wenzel HJ, Schwartzkroin PA, Palmiter RD.2000. Seizures and neuronal damage in mice lacking vesicularzinc. Epilepsy Res 39:153–169.

Cole TB, Martyanova A, Palmiter RD. 2001. Removing zinc fromsynaptic vesicles does not impair spatial learning, memory, orsensorimotor functions in the mouse. Brain Res 891:253–265.

Coleman JE. 1992. Zinc proteins: enzymes, storage proteins, tran-scription factors, and replication proteins. Annu Rev Biochem61:897–946.

Colvin RA, Fontaine CP, Laskowski M, Thomas D. 2003. Zn21transporters and Zn21 homeostasis in neurons. Eur J Pharmacol479:171–185.

Colvin RA, Bush AI, Volitakis I, Fontaine CP, Thomas D, KikuchiK, Holmes WR. 2008. Insights into Zn21 homeostasis in neuronsfrom experimental and modeling studies. Am J Physiol Cell Phys-iol 294:C726–C742.

Cornett CR, Markesbery WR, Ehmann WD. 1998. Imbalances oftrace elements related to oxidative damage in Alzheimer’s diseasebrain. Neurotoxicology 19:339–345.

Corrigan FM, Reynolds GP, Ward NI. 1993. Hippocampal tin, alumi-num and zinc in Alzheimer’s disease. Biometals 6:149–154.

Coulter DA. 2000. Mossy fiber zinc and temporal lobe epilepsy:Pathological association with altered ‘‘epileptic’’ gamma-aminobu-tyric acid A receptors in dentate granule cells. Epilepsia 41(Suppl 6):S96–S99.

Cousins RJ. 1998. A role of zinc in the regulation of gene expres-sion. Proc Nutr Soc 57:307–311.

Cousins RJ, Liuzzi JP, Lichten LA. 2006. Mammalian zinc trans-port, trafficking, and signals. J Biol Chem 281:24085–24089.

Coyle JT, Puttfarcken P. 1993. Oxidative stress, glutamate, and neu-rodegenerative disorders. Science 262:689–695.

Cragg RA, Christie GR, Phillips SR, Russi RM, Kury S, MathersJC, Taylor PM, Ford D. 2002. A novel zinc-regulated human zinctransporter, hZTL1, is localized to the enterocyte apical mem-brane. J Biol Chem 277:22789–22797.

Crossthwaite AJ, Hasan S, Williams RJ. 2002. Hydrogen peroxide-mediated phosphorylation of ERK1/2. Akt/PKB and JNK incortical neurones: Dependence on Ca(21) and PI3-kinase. J Neu-rochem 80:24–35.

Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS. 1997.Decreased zinc affinity of amyotrophic lateral sclerosis-associatedsuperoxide dismutase mutants leads to enhanced catalysis of tyro-sine nitration by peroxynitrite. J Neurochem 69:1936–1944.

Cuajungco MP, Lees GJ. 1997. Zinc and Alzheimer’s disease: Isthere a direct link? Brain Res Rev 23:219–236.

Cuajungco MP, Faget KY. 2003. Zinc takes the center stage: Its par-adoxical role in Alzheimer’s disease. Brain Res Brain Res Rev41:44–56.

Cunningham MG, Ames HM, Christensen MK, Sorensen JC. 2007.Zincergic innervation of medial prefrontal cortex by basolateralprojection neurons. Neuroreport 18:531–535.

Danscher G, Howell G, Perez-Clausell J, Hertel N. 1985. The dithi-zone. Timm’s sulphide silver and the selenium methods demon-strate a chelatable pool of zinc in CNS. A proton activation(PIXE) analysis of carbon tetrachloride extracts from rat brainsand spinal cords intravitally treated with dithizone. Histochemis-try 83:419–422.

Danscher G, Jensen KB, Frederickson CJ, Kemp K, Andreasen A,Juhl S, Stoltenberg M, Ravid R. 1997. Increased amount of zinc


Synapse

in the hippocampus and amygdala of Alzheimer’s diseasedbrains: A proton-induced X-ray emission spectroscopic analysis ofcryostat sections from autopsy material. J Neurosci Methods76:53–59.

Danscher G, Wang Z, Kim YK, Kim SJ, Sun Y, Jo SM. 2003. Immu-nocytochemical localization of zinc transporter 3 in the ependymaof the mouse spinal cord. Neurosci Lett 342:81–84.

Daumas S, Halley H, Lassalle JM. 2004. Disruption of hippocampalCA3 network: Effects on episodic-like memory processing inC57BL/6J mice. Eur J Neurosci 20:597–600.

Davis SR, Cousins RJ. 2000. Metallothionein expression in animals:A physiological perspective on function. J Nutr 130:1085–1088.

Deibel MA, Ehmann WD, Markesbery WR. 1996. Copper, iron, andzinc imbalances in severely degenerated brain regions in Alzhei-mer’s disease: Possible relation to oxidative stress. J Neurol Sci143:137–142.

Dineley KE, Votyakova TV, Reynolds IJ. 2003. Zinc inhibition of cel-lular energy production: Implications for mitochondria and neuro-degeneration. J Neurochem 85:563–570.

Dineley KE, Richards LL, Votyakova TV, Reynolds IJ. 2005. Zinccauses loss of membrane potential and elevates reactive oxygenspecies in rat brain mitochondria. Mitochondrion 5:55–65.

Dominguez MI, Blasco-Ibanez JM, Crespo C, Marques-Mari AI,Martinez-Guijarro FJ. 2003. Zinc chelation during non-lesioningoverexcitation results in neuronal death in the mouse hippocam-pus. Neuroscience 116:791–806.

Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G,Carey PR. 2003. Metal binding and oxidation of amyloid-betawithin isolated senile plaque cores: Raman microscopic evidence.Biochemistry 42:2768–2773.

Doraiswamy PM, Finefrock AE. 2004. Metals in our minds: Thera-peutic implications for neurodegenerative disorders. Lancet Neu-rol 3:431–434.

Draguhn A, Verdorn TA, Ewert M, Seeburg PH, Sakmann B. 1990.Functional and molecular distinction between recombinant ratGABAA receptor subtypes by Zn21 Neuron 5:781–788.

Drevets WC, Price JL, Furey ML. 2008. Brain structural and func-tional abnormalities in mood disorders: Implications for neurocir-cuitry models of depression. Brain Struct Funct 213:93–118.

Dudek FE. 2001. Zinc and epileptogenesis. Epilepsy Curr 1:66–70.Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton

M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN,Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S. 1996.Increased amyloid-beta42(43) in brains of mice expressing mutantpresenilin 1. Nature 383:710–713.

Duman RS, Heninger GR, Nestler EJ. 1997. A molecular and cellu-lar theory of depression. Arch Gen Psychiatry 54:597–606.

Dvergsten CL, Fosmire GJ, Ollerich DA, Sandstead HH. 1983.Alterations in the postnatal development of the cerebellar cortexdue to zinc deficiency. I. Impaired acquisition of granule cells.Brain Res 271:217–226.

Dvergsten CL, Johnson LA, Sandstead HH. 1984a. Alterations inthe postnatal development of the cerebellar cortex due to zincdeficiency. III. Impaired dendritic differentiation of basket andstellate cells. Brain Res 318:21–26.

Dvergsten CL, Fosmire GJ, Ollerich DA, Sandstead HH. 1984b.Alterations in the postnatal development of the cerebellar cortexdue to zinc deficiency. II. Impaired maturation of Purkinje cells.Brain Res 318:11–20.

Dyck R, Beaulieu C, Cynader M. 1993. Histochemical localization ofsynaptic zinc in the developing cat visual cortex. J Comp Neurol329:53–67.

Ebadi M, Murrin LC, Pfeiffer RF. 1990. Hippocampal zinc thioneinand pyridoxal phosphate modulate synaptic functions. Ann N YAcad Sci 585:189–201.

Eide DJ. 2004. The SLC39 family of metal ion transporters. PflugersArch 447:796–800.

Eide DJ. 2006. Zinc transportzers and the cellular trafficking ofzinc. Biochim Biophys Acta 1763:711–722.

Emerit J, Edeas M, Bricaire F. 2004. Neurodegenerative diseasesand oxidative stress. Biomed Pharmacother 58:39–46.

Erickson JC, Hollopeter G, Thomas SA, Froelick GJ, Palmiter RD.1997. Disruption of the metallothionein-III gene in mice: Analysisof brain zinc, behavior, and neuron vulnerability to metals, aging,and seizures. J Neurosci 17:1271–1281.

Ermilova IP, Ermilov VB, Levy M, Ho E, Pereira C, Beckman JS.2005. Protection by dietary zinc in ALS mutant G93A SOD trans-genic mice. Neurosci Lett 379:42–46.

Estevez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, RichardsonGJ, Tarpey MM, Barbeito L, Beckman JS. 1999. Induction ofnitric oxide-dependent apoptosis in motor neurons by zinc-defi-cient superoxide dismutase. Science 286:2498–2500.

Fisher JL. 2002. A histidine residue in the extracellular N-terminaldomain of the GABA(A) receptor alpha5 subunit regulates sensi-tivity to inhibition by zinc. Neuropharmacology 42:922–928.

Fisher JL, Macdonald RL. 1998. The role of an alpha subtype M2-M3 His in regulating inhibition of GABAA receptor current byzinc and other divalent cations. J Neurosci 18:2944–2953.

Flynn C, Brown CE, Galasso SL, McIntyre DC, Teskey GC, DyckRH. 2007. Zincergic innervation of the forebrain distinguishesepilepsy-prone from epilepsy-resistant rat strains. Neuroscience144:1409–1414.

Foresti ML, Arisi GM, Fernandes A, Tilelli CQ, Garcia-Cairasco N.2008. Chelatable zinc modulates excitability and seizure durationin the amygdala rapid kindling model. Epilepsy Res 79: 166–172.

Forsythe ID, Westbrook GL, Mayer ML. 1988. Modulation of excita-tory synaptic transmission by glycine and zinc in cultures ofmouse hippocampal neurons. J Neurosci 8:3733–3741.

Fraker PJ. 2005. Roles for cell death in zinc deficiency. J Nutr135:359–362.

Fraker PJ, Telford WG. 1997. A reappraisal of the role of zinc in lifeand death decisions of cells. Proc Soc Exp Biol Med 215:229–236.

Fraker PJ, King LE, Laakko T, Vollmer TL. 2000. The dynamic linkbetween the integrity of the immune system and zinc status.J Nutr 130(5 Suppl):1399S–1406S.

Franco-Pons N, Casanovas-Aguilar C, Arroyo S, Rumia J, Perez-Clausell J, Danscher G. 2000. Zinc-rich synaptic boutons inhuman temporal cortex biopsies. Neuroscience 98:429–435.

Franck JE, Pokorny J, Kunkel DD, Schwartzkroin PA. 1995. Physio-logic and morphologic characteristics of granule cell circuitry inhuman epileptic hippocampus. Epilepsia 36:543–558.

Frederickson CJ. 1989. Neurobiology of zinc and zinc-containingneurons. Int Rev Neurobiol 31:145–238.

Frederickson CJ, Moncrieff DW. 1994. Zinc-containing neurons. BiolSignals 3:127–139.

Frederickson CJ, Bush AI. 2001. Synaptically released zinc: Physio-logical functions and pathological effects. Biometals 14:353–366.

Frederickson CJ, Hernandez MD, Goik SA, Morton JD, McGinty JF.1988. Loss of zinc staining from hippocampal mossy fibers duringkainic acid induced seizures: A histofluorescence study. Brain Res446:383–386.

Frederickson RE, Frederickson CJ, Danscher G. 1990. In situ bind-ing of bouton zinc reversibly disrupts performance on a spatialmemory task. Behav Brain Res 38:25–33.

Frederickson CJ, Rampy BA, Reamy-Rampy S, Howell GA. 1992.Distribution of histochemically reactive zinc in the forebrain ofthe rat. J Chem Neuroanat 5:521–530.

Frederickson CJ, Suh SW, Silva D, Frederickson CJ, Thompson RB.2000. Importance of zinc in the central nervous system: The zinc-containing neuron. J Nutr 130(5S Suppl):1471S–1483S.

Frederickson CJ, Koh JY, Bush AI. 2005a. The neurobiology of zincin health and disease. Nat Rev Neurosci 6:449–462.

Frederickson CJ, Hershfinkel M, Giblin L. 2005b. The gluzinergicsynapse: who’s talking and who’s listening? In: Stanton PK,Bramham C, Scharfman HE, editors. Synaptic plasticity andtranssynaptic signaling. New York: Springer. p 123–137.

Frederickson CJ, Giblin LJ, Krezel A, McAdoo DJ, Mueller RN,Zeng Y, Balaji RV, Masalha R, Thompson RB, Fierke CA, SarveyJM, de Valdenebro M, Prough DS, Zornow MH. 2006. Concentra-tions of extracellular free zinc (pZn)e in the central nervoussystem during simple anesthetization, ischemia and reperfusion.Exp Neurol 198:285–293.

Friedlich AL, Lee JY, van Groen T, Cherny RA, Volitakis I, Cole TB,Palmiter RD, Koh JY, Bush AI. 2004. Neuronal zinc exchangewith the blood vessel wall promotes cerebral amyloid angiopathyin an animal model of Alzheimer’s disease. J Neurosci 24:3453–3459.

Fukahori M, Itoh M. 1990. Effects of dietary zinc status on seizuresusceptibility and hippocampal zinc content in the El (epilepsy)mouse. Brain Res 529:16–22.

Fukahori M, Itoh M, Oomagari K, Kawasaki H. 1988. Zinc contentin discrete hippocampal and amygdaloid areas of the epilepsy (El)mouse and normal mice. Brain Res 455:381–384.

Fukamachi Y, Karasaki Y, Sugiura T, Itoh H, Abe T, Yamamura K,Higashi K. 1998. Zinc suppresses apoptosis of U937 cells inducedby hydrogen peroxide through an increase of the Bcl-2/Bax ratio.Biochem Biophys Res Commun 246:364–369.

Gaeta A, Hider RC. 2005. The crucial role of metal ions in neurode-generation: The basis for a promising therapeutic strategy. Br JPharmacol 146:1041–1059.

Gaither LA, Eide DJ. 2000. Functional expression of the humanhZIP2 zinc transporter. J Biol Chem 275:5560–5564.

Gaither LA, Eide DJ. 2001. Eukaryotic zinc transporters and theirregulation. Biometals 14:251–270.


Synapse

Galasso SL, Dyck RH. 2007. The role of zinc in cerebral ischemia.Mol Med 13:380–387.

Gardner JM, Powell CA, Baker-Henningham H, Walker SP, ColeTJ, Grantham-McGregor SM. 2005. Zinc supplementation andpsychosocial stimulation: Effects on the development of under-nourished Jamaican children. Am J Clin Nutr 82:399–405.

Garrett B, Slomianka L. 1992. Postnatal development of zinc-containing cells and neuropil in the visual cortex of the mouse.Anat Embryol (Berl) 186:487–496.

Gill CH, Peters JA, Lambert JJ. 1995. An electrophysiological inves-tigation of the properties of a murine recombinant 5-HT3 receptorstably expressed in HEK 293 cells. Br J Pharmacol 114:1211–1221.

Gimenez-Llort L, Blazquez G, Canete T, Johansson B, Oddo S, TobenaA, LaFerla FM, Fernandez-Teruel A. 2007. Modeling behavioraland neuronal symptoms of Alzheimer’s disease in mice: A role forintraneuronal amyloid. Neurosci Biobehav Rev 31:125–147.

Giralt M, Molinero A, Carrasco J, Hidalgo J. 2000. Effect of dietaryzinc deficiency on brain metallothionein-I and -III mRNA levelsduring stress and inflammation. Neurochem Int 36:555–562.

Giralt M, Penkowa M, Lago N, Molinero A, Hidalgo J. 2002. Metal-lothionein-112 protect the CNS after a focal brain injury. ExpNeurol 173:114–128.

Gombos Z, Spiller A, Cottrell GA, Racine RJ, McIntyre Burnham W.1999. Mossy fiber sprouting induced by repeated electroconvulsiveshock seizures. Brain Res 844:28–33.

Gong YH, Elliott JL. 2000. Metallothionein expression is altered ina transgenic murine model of familial amyotrophic lateral sclero-sis. Exp Neurol 162:27–36.

Gong H, Takami Y, Amemiya T, Tozu M, Ohashi Y. 2004. Ocularsurface in Zn-deficient rats. Ophthalmic Res 36:129–138.

Lewis DA, Gonzalez-Burgos G. 2006. Pathophysiologically basedtreatment interventions in schizophrenia. Nat Med 12:1016–1022.

Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J. 2008. Subu-nit-specific trafficking of GABA(A) receptors during status epilep-ticus. J Neurosci 28:2527–2538.

Gorter JA, Petrozzino JJ, Aronica EM, Rosenbaum DM, Opitz T,Bennett MV, Connor JA, Zukin RS. 1997. Global ischemia inducesdownregulation of Glur2 mRNA and increases AMPA receptor-mediated Ca21 influx in hippocampal CA1 neurons of gerbil.J Neurosci 17:6179–6188.

Gould TD, Manji HK. 2005. Glycogen synthase kinase-3: A putativemolecular target for lithium mimetic drugs. Neuropsychopharma-cology 30:1223–1237.

Grahn BH, Paterson PG, Gottschall-Pass KT, Zhang Z. 2001. Zincand the eye. J Am Coll Nutr 20:106–118.

Hager LJ, Palmiter RD. 1981. Transcriptional regulation of mouseliver metallothionein-I gene by glucocorticoids. Nature 291:340–342.

Halas ES, Eberhardt MJ, Diers MA, Sandstead HH. 1983. Learningand memory impairment in adult rats due to severe zinc defi-ciency during lactation. Physiol Behav 30:371–381.

Halas ES, Hunt CD, Eberhardt MJ. 1986. Learning and memorydisabilities in young adult rats from mildly zinc deficient dams.Physiol Behav 37:451–458.

Hamed SA, Abdellah MM. 2004. Trace elements and electrolyteshomeostasis and their relation to antioxidant enzyme activity inbrain hyperexcitability of epileptic patients. J Pharmacol Sci96:349–359.

Hamer DH. 1986. Metallothionein. Annu Rev Biochem 55:913–951.Harrison PJ. 2004. The hippocampus in schizophrenia: A review of

the neuropathological evidence and its pathophysiological implica-tions. Psychopharmacology (Berl) 174:151–162.

Harrison NL, Gibbons SJ. 1994. Zn21: An endogenous modulator ofligand- and voltage-gated ion channels. Neuropharmacology33:935–952.

Harrison PJ, Weinberger DR. 2005. Schizophrenia genes, geneexpression, and neuropathology: On the matter of their conver-gence. Mol Psychiatry 10:40–68.

Hensley K, Aksenova M, Carney JM, Harris M, Butterfield DA.1995. Amyloid beta-peptide spin trapping. I. Peptide enzymetoxicity is related to free radical spin trap reactivity. Neuroreport6:489–492.

Hershkovitz E, Printzman L, Segev Y, Levy J, Phillip M. 1999. Zincsupplementation increases the level of serum insulin-like growthfactor-I but does not promote growth in infants with nonorganicfailure to thrive. Horm Res 52:200–204.

Hidalgo J, Aschner M, Zatta P, Vasak M. 2001. Roles of the metallo-thionein family of proteins in the central nervous system. BrainRes Bull 55:133–145.

Hirzel K, Muller U, Latal AT, Hulsmann S, Grudzinska J, SeeligerMW, Betz H, Laube B. 2006. Hyperekplexia phenotype of glycine

receptor alpha1 subunit mutant mice identifies Zn(21) as anessential endogenous modulator of glycinergic neurotransmission.Neuron 52:679–690.

Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P,Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C,O’Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K,Duff K. 1998. Accelerated Alzheimer-type phenotype in transgenicmice carrying both mutant amyloid precursor protein and preseni-lin 1 transgenes. Nat Med 4:97–100.

Howell GA, Welch MG, Frederickson CJ. 1984. Stimulation-induceduptake and release of zinc in hippocampal slices. Nature 308:736–738.

Howell GA, Perez-Clausell J, Frederickson CJ. 1991. Zinc contain-ing projections to the bed nucleus of the stria terminalis. BrainRes 562:181–189.

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S,Yang F, Cole G. 1996. Correlative memory deficits. Abetaelevation, and amyloid plaques in transgenic mice. Science 274:99–102.

Hsiao B, Dweck D, Luetje CW. 2001. Subunit-dependent modulationof neuronal nicotinic receptors by zinc. J Neurosci 21:1848–1856.

Huang L, Kirschke CP, Gitschier J. 2002. Functional characteriza-tion of a novel mammalian zinc transporter, ZnT6. J Biol Chem277:26389–26395.

Huang L, Kirschke CP, Zhang Y, Yu YY. 2005. The ZIP7 gene(Slc39a7) encodes a zinc transporter involved in zinc homeostasisof the Golgi apparatus. J Biol Chem 280:15456–15463.

Huang X, Atwood CS, Moir RD, Hartshorn MA, Vonsattel JP, TanziRE, Bush AI. 1997. Zinc-induced Alzheimer’s Abeta1–40 aggrega-tion is mediated by conformational factors. J Biol Chem272:26464–26470.

Huang X, Cuajungco MP, Atwood CS, Moir RD, Tanzi RE, Bush AI.2000. Alzheimer’s disease, beta-amyloid protein and zinc. J Nutr130(5S Suppl):1488S–1492S.

Huang YZ, Pan E, Xiong ZQ, McNamara JO. 2008. Zinc-mediatedtransactivation of TrkB potentiates the hippocampal mossy fiber-CA3 pyramid synapse. Neuron 57:546–558.

Hubbard PC, Lummis SC. 2000. Zn(21) enhancement of therecombinant 5-HT(3) receptor is modulated by divalent cations.Eur J Pharmacol 394:89–197.

Ibs KH, Rink L. 2003. Zinc-altered immune function. J Nutr 133(5Suppl 1):1452S–1456S.

Ilouz R, Kaidanovich O, Gurwitz D, Eldar-Finkelman H. 2002. Inhi-bition of glycogen synthase kinase-3beta by bivalent zinc ions:Insight into the insulin-mimetic action of zinc. Biochem BiophysRes Commun 295:102–106.

Ishida N, Kasamo K, Nakamoto Y, Suzuki J. 1993. Epileptic seizureof El mouse initiates at the parietal cortex: Depth EEG observa-tion in freely moving condition using buffer amplifier. Brain Res608:52–57.

Itoh M, Ebadi M. 1982. The selective inhibition of hippocampalglutamic acid decarboxylase in zinc-induced epileptic seizures.Neurochem Res 7:1287–1298.

Jankowski-Hennig MA, Clegg MS, Daston GP, Rogers JM, Keen CL.2000. Zinc-deficient rat embryos have increased caspase 3-likeactivity and apoptosis. Biochem Biophys Res Commun 271:250–256.

Jia Y, Jeng JM, Sensi SL, Weiss JH. 2002. Zn21 currents are medi-ated by calcium-permeable AMPA/kainate channels in culturedmurine hippocampal neurones. J Physiol 543(Pt 1):35–48.

Jiang L-J, Maret W, Vallee B. 1998. The glutathione redox couplemodulates zinc transfer from metallothionein to zinc-depleted sor-bitol dehydrogenase. Proc Natl Acad Sci USA 95:3483–3488.

Jo SM, Won MH, Cole TB, Jensen MS, Palmiter RD, Danscher G.2000a. Zinc-enriched (ZEN) terminals in mouse olfactory bulb.Brain Res 865:227–236.

Jo SM, Danscher G, Daa Schrøder H, Won MH, Cole TB. 2000b.Zinc-enriched (ZEN) terminals in mouse spinal cord: Immunohis-tochemistry and autometallography. Brain Res 870:163–169.

Kagi HR. 1993. Evolution, structure and chemical activity of classI metallothioneins: An overview. In: Suzuki KT, Imura N, KimuraM, editors. Metallothionein III. Berlin: Birkhauser Verlag.p 29–55.

Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, SugiuraN, Sasaki R, Mori K, Iwanaga T, Nagao M. 2002. Cloning andcharacterization of a novel mammalian zinc transporter, zinctransporter 5, abundantly expressed in pancreatic beta cells.J Biol Chem 277:19049–19055.

Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M. 2004. Overview ofmammalian zinc transporters. Cell Mol Life Sci 61:49–68.

Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R. 2005.Neurotrophin levels in postmortem brains of suicide victims and


Synapse

the effects of antemortem diagnosis and psychotropic drugs. BrainRes Mol Brain Res 136:29–37.

Karin M, Eddy RL, Henry WM, Haley LL, Byers MG, Shows TB.1984. Human metallothionein genes are clustered on chromosome16. Proc Natl Acad Sci USA 81:5494–5498.

Kay AR, Toth K. 2008. Is zinc a neuromodulator? Sci Signal 1:re3.Kim EY, Koh JY, Kim YH, Sohn S, Joe E, Gwag BJ. 1999a. Zn21

entry produces oxidative neuronal necrosis in cortical cellcultures. Eur J Neurosci 11:327–334.

Kim YH, Kim EY, Gwag BJ, Sohn S, Koh JY. 1999b. Zinc-inducedcortical neuronal death with features of apoptosis and necrosis:Mediation by free radicals. Neuroscience 89:175–182.

Kim TY, Hwang JJ, Yun SH, Jung MW, Koh JY. 2002. Augmenta-tion by zinc of NMDA receptor-mediated synaptic responses inCA1 of rat hippocampal slices: Mediation by Src family tyrosinekinases. Synapse 46:49–56.

Kirschke CP, Huang L. 2003. ZnT7, a novel mammalian zinc trans-porter, accumulates zinc in the Golgi apparatus. J Biol Chem278:4096–4102.

Kitamura Y, Iida Y, Abe J, Mifune M, Kasuya F, Ohta M, Igarashi K,Saito Y, Saji H. 2006. Release of vesicular Zn21 in a rat transientmiddle cerebral artery occlusion model. Brain Res Bull 69:622–625.

Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. 2005.Lipopolysaccharide-induced inflammation exacerbates tau pathol-ogy by a cyclin-dependent kinase 5-mediated pathway in a trans-genic model of Alzheimer’s disease. J Neurosci 25:8843–8853.

Klein C, Sunahara RK, Hudson TY, Heyduk T, Howlett AC. 2002.Zinc inhibition of cAMP signaling. J Biol Chem 277:11859–11865.

Klein C, Heyduk T, Sunahara RK. 2004. Zinc inhibition of adenylylcyclase correlates with conformational changes in the enzyme.Cell Signal 16:1177–1185.

Kodirov SA, Takizawa S, Joseph J, Kandel ER, Shumyatsky GP,Bolshakov VY. 2006. Synaptically released zinc gates long-termpotentiation in fear conditioing pathways. Proc Natl Acad SciUSA 103:15218–15223.

Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW. 1996. Therole of zinc in selective neuronal death after transient global cere-bral ischemia. Science 272:1013–1016.

Kohr G, Mody I. 1994. Kindling increases N-methyl-D-aspartate po-tency at single N-methyl-D-aspartate channels in dentate gyrusgranule cells. Neuroscience 62:975–981.

Kroczka B, Zieba A, Dudek D, Pilc A, Nowak G. 2000. Zinc exhibitsan antidepressant-like effect in the forced swimming test in mice.Pol J Pharmacol 52:403–406.

Kroczka B, Branski P, Palucha A, Pilc A, Nowak G. 2001. Antide-pressant-like properties of zinc in rodent forced swim test. BrainRes Bull 55:297–300.

Kunzmann A, Dedoussis G, Jajte J, Malavolta M, Mocchegiani E,Burkle A. 2008. Effect of zinc on cellular poly(ADP-ribosylationcapacity. Exp Gerontol 43:409–414.

Lamont SR, Paulls A, Stewart CA. 2001. Repeated electroconvulsivestimulation, but not antidepressant drugs, induces mossy fibresprouting in the rat hippocampus. Brain Res 893:53–58.

Land PW, Akhtar ND. 1999. Experience-dependent alteration ofsynaptic zinc in rat somatosensory barrel cortex. Somatosens MotRes 16:139–150.

Land PW, Shamalla-Hannah L. 2001. Transient expression of synap-tic zinc during development of uncrossed retinogeniculate projec-tions. J Comp Neurol 433:515–525.

Land PW, Shamalla-Hannah L. 2002. Experience-dependent plastic-ity of zinc-containing cortical circuits during a critical period ofpostnatal development. J Comp Neurol 447:43–56.

Larson AA, Kitto KF. 1997. Manipulations of zinc in the spinal cord,by intrathecal injection of zinc chloride, disodium-calcium-EDTA,or dipicolinic acid, alter nociceptive activity in mice. J PharmacolExp Ther 282:1319–1325.

Larson AA, Kitto KF. 1999. Chelation of zinc in the extracellulararea of the spinal cord, using ethylenediaminetetraacetic acid di-sodium-calcium salt or dipicolinic acid, inhibits the antinocicep-tive effect of capsaicin in adult mice. J Pharmacol Exp Ther288:759–765.

Lassalle JM, Bataille T, Halley H. 2000. Reversible inactivation ofthe hippocampal mossy fiber synapses in mice impairs spatiallearning, but neither consolidation nor memory retrieval, in theMorris navigation task. Neurobiol Learn Mem 73:243–257.

Laube B. 2002. Potentiation of inhibitory glycinergic neurotransmis-sion by Zn21: A synergistic interplay between presynaptic P2X2and postsynaptic glycine receptors. Eur J Neurosci 16:1025–1036.

Lavoie N, Peralta MR III, Chiasson M, Lafortune K, Pellegrini L,Seress L, Toth K. 2007. Extracellular chelation of zinc does notaffect hippocampal excitability and seizure-induced cell death inrats. J Physiol 578(Pt 1):275–289.

Lee JY, Mook-Jung I, Koh JY. 1999. Histochemically reactive zinc inplaques of the Swedish mutant beta-amyloid precursor proteintransgenic mice. J Neurosci 19:RC10.

Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. 2002a. Contribu-tion by synaptic zinc to the gender-disparate plaque formation inhuman Swedish mutant APP transgenic mice. Proc Natl Acad SciUSA 99:7705–7710.

Lee JM, Zipfel GJ, Park KH, He YY, Hsu CY, Choi DW. 2002b. Zinctranslocation accelerates infarction after mild transient focalischemia. Neuroscience 115:871–878.

Lee JY, Friedman JE, Angel I, Kozak A, Koh JY. 2004. The lipo-philic metal chelator DP-109 reduces amyloid pathology in brainsof human beta-amyloid precursor protein transgenic mice. Neuro-biol Aging 25:1315–1321.

Lengyel I, Fieuw-Makaroff S, Hall AL, Sim AT, Rostas JA, DunkleyPR. 2000. Modulation of the phosphorylation and activity of cal-cium/calmodulin-dependent protein kinase II by zinc. J Neuro-chem 75:594–605.

Lewis DA, Hashimoto T. 2007. Deciphering the disease process ofschizophrenia: The contribution of cortical gaba neurons. Int RevNeurobiol 78:109–131.

Li Y, Hough CJ, Suh SW, Sarvey JM, Frederickson CJ. 2001. Rapidtranslocation of Zn(21) from presynaptic terminals into postsy-naptic hippocampal neurons after physiological stimulation.J Neurophysiol 86:2597–2604.

Lin DD, Cohen AS, Coulter DA. 2001. Zinc-induced augmentation ofexcitatory synaptic currents and glutamate receptor responses inhippocampal CA3 neurons. J Neurophysiol 85:1185–1196.

Link TA, von Jagow G. 1995. Zinc ions inhibit the QP center of bo-vine heart mitochondrial bc1 complex by blocking a protonatablegroup. J Biol Chem 270:25001–25006.

Linkous DH, Flinn JM, Koh JY, Lanzirotti A, Bertsch PM, JonesBF, Giblin LJ, Frederickson CJ. 2008. Evidence that the ZNT3protein controls the total amount of element al zinc in synapticvesicles. J Histochem Cytochem 56:3–6.

Liochev SI, Chen LL, Hallewell RA, Fridovich I. 1997. Superoxide-dependent peroxidase activity of H48Q: A superoxide dismutasevariant associated with familial amyotrophic lateral sclerosis.Arch Biochem Biophys 346:263–268.

Lipska BK. 2004. Using animal models to test a neurodevelopmentalhypothesis of schizophrenia. J Psychiatry Neurosci 29:282–286.

Lipska BK, Weinberger DR. 2000. To model a psychiatric disorderin animals: Schizophrenia as a reality test. Neuropsychopharma-cology 23:223–239.

Liuzzi JP, Cousins RJ. 2004. Mammalian zinc transporters. AnnuRev Nutr 24:151–172.

Long Y, Hardwick AL, Frederickson CJ. 1995. Zinc-containinginnervation of the subicular region in the rat. Neurochem Int27:95–103.

Lopantsev V, Wenzel HJ, Cole TB, Palmiter RD, Schwartzkroin PA.2001. Lack of vesicular zinc in mossy fibers does not affect synap-tic excitability of CA3 pyramidal cells in zinc transporter 3 knock-out mice. Neuroscience 116:237–248.

Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, MarkesberyWR. 1998. Copper, iron and zinc in Alzheimer’s disease senileplaques. J Neurol Sci 158:47–52.

Lu YM, Yin HZ, Chiang J, Weiss JH. 1996. Ca(21)-permeableAMPA/kainate and NMDA channels: High rate of Ca21 influxunderlies potent induction of injury. J Neurosci 16:5457–5465.

Lu YM, Taverna FA, Tu R, Ackerley CA, Wang YT, Roder J. 2000.Endogenous Zn(21) is required for the induction of long-termpotentiation at rat hippocampal mossy fiber-CA3 synapses.Synapse 38:187–197.

Lyons TJ, Nersissian A, Huang H, Yeom H, Nishida CR, Graden JA,Gralla EB, Valentine JS. 2000. The metal binding properties of thezinc site of yeast copper-zinc superoxide dismutase: Implications foramyotrophic lateral sclerosis. J Biol Inorg Chem 5:189–203.

Macdonald RS. 2000. The role of zinc in growth and cell prolifera-tion. J Nutr 130(5S Suppl):1500S–1508S.

Macdonald RL, Kapur J. 1999. Acute cellular alterations in the hip-pocampus after status epilepticus. Epilepsia 40(Suppl 1):S9–S20.

Macdonald RL, Olsen RW. 1994. GABAA receptor channels. AnnuRev Neurosci 17:569–602.

Mackay-Sim A, Dreosti IE. 1989. Olfactory function in zinc-deficientadult mice. Exp Brain Res 76:207–212.

Mackenzie GG, Oteiza PI. 2007. Zinc and the cytoskeleton in theneuronal modulation of transcription factor NFAT. J Cell Physiol210:246–256.

Mackenzie GG, Zago MP, Keen CL, Oteiza PI. 2002. Low intracellu-lar zinc impairs the translocation of activated NF-kappa B to thenuclei in human neuroblastoma IMR-32 cells. J Biol Chem277:34610–34617.


Synapse

Mackenzie GG, Keen CL, Oteiza PI. 2006. Microtubules arerequired for NF-kappaB nuclear translocation in neuroblastomaIMR-32 cells: Modulation by zinc. J Neurochem 99:402–415.

Maes M, D’Haese PC, Scharpe S, D’Hondt PD, Cosyns P, De Broe ME.1994. Hypozincemia in depression. J Affect Disord 31:135–140.

Maes M, Vandoolaeghe E, Neels H, Demedts P, Wauters A, MeltzerHY, Altamura C, Desnyder R. 1997. Lower serum zinc in majordepression is a selective marker of resistance and of the immune/inflammatory response in that illness. Biol Psychiatry 42:349–358.

Malaiyandi LM, Honick AS, Rintoul GL, Wang QJ, Reynolds IJ.2005. Zn2+ inhibits mitochondrial movement in neurons by phos-phatidylinositol 3-kinase activation. J Neurosci 25:9507–9514.

Mandava P, Howell GA, Frederickson CJ. 1993. Zinc-containingneuronal innervation of the septal nuclei. Brain Res 608:115–122.

Marcellini F, Giuli C, Papa R, Gagliardi C, Dedoussis G, Herbein G,Fulop T, Monti D, Rink L, Jajte J, Mocchegiani E. 2006. Zincstatus, psychological and nutritional assessment in old peoplerecruited in five European countries: Zincage study. Biogerontol-ogy 7:339–345.

Maret W. 1995. Metallothionein/disulfide interactions, oxidativestress, and the mobilization of cellular zinc. Neurochem Int27:111–117.

Maret W. 2000. The function of zinc metallothionein: A link betweencellular zinc and redox state. J Nutr 130(5S Suppl):1455S–1458S.

Maret W, Vallee BL. 1998. Thiolate ligands in metallothionein con-fer redox activity on zinc clusters. Proc Natl Acad Sci USA95:3478–3482.

Markesbery WR. 1997. Oxidative stress hypothesis in Alzheimer’sdisease. Free Radic Biol Med 23:134–147.

Martin SJ, Grimwood PD, Morris RG. 2000. Synaptic plasticity andmemory: An evaluation of the hypothesis. Annu Rev Neurosci23:649–711.

Maske H. 1955. Uber den topochemischen Nachweis von Zink imAmmonshorn verschiedener Saugetiere. Naturwissenschaften 42:424.

Masters BA, Quaife CJ, Erickson JC, Kelly EJ, Froelick GJ,Zambrowicz BP, Brinster RL, Palmiter RD. 1994. MetallothioneinIII is expressed in neurons that sequester zinc in synapticvesicles. J Neurosci 14:5844–5857.

Mattson MP, Meffert MK. 2006. Roles for NF-kappaB in nerve cellsurvival, plasticity, and disease. Cell Death Differ 13:852–860.

Mayberg HS. 2007. Defining the neural circuitry of depression:Toward a new nosology with therapeutic implications. Biol Psychi-atry 61:729–730.

Mayer ML, Vyklicky L Jr. 1989. The action of zinc on synaptictransmission and neuronal excitability in cultures of mouse hippo-campus. J Physiol 415:351–365.

McBain CJ, Dingledine R. 1993. Heterogeneity of synaptic gluta-mate receptors on CA3 stratum radiatum interneurones of rathippocampus. J Physiol 462:373–392.

McClain CJ, Su LC, Gilbert H, Cameron D. 1983. Zinc-deficiency-induced retinal dysfunction in Crohn’s disease. Dig Dis Sci 28:85–87.

McLaughlin B, Pal S, Tran MP, Parsons AA, Barone FC, ErhardtJA, Aizenman E. 2001. p38 activation is required upstream ofpotassium current enhancement and caspase cleavage in thiol oxi-dant-induced neuronal apoptosis. J Neurosci 21:3303–3311.

McLoughlin IJ, Hodge SJ. 1990. Zinc in depressive disorder. ActaPsychiatr Scand 82:451–453.

McMahon RJ, Cousins RJ. 1998. Regulation of the zinc transporterZnT-1 by dietary zinc. Proc Natl Acad Sci USA 95:4841–4846.

McNall AD, Etherton TD, Fosmire GJ. 1995. The impaired growthinduced by zinc deficiency in rats is associated with decreasedexpression of the hepatic insulin-like growth factor I and growthhormone receptor genes. J Nutr 125:874–879.

Meloni G, Faller P, Vasak M. 2007. Redox silencing of copper inmetal-linked neurodegenerative disorders: Reaction of Zn7metal-lothionein-3 with Cu21 ions. J Biol Chem 282:16068–16078.

Meloni G, Sonois V, Delaine T, Guilloreau L, Gillet A, Teissie J,Faller P, Vasak M. 2008. Metal swap between Zn7-metallothio-nein-3 and amyloid-beta-Cu protects against amyloid-beta toxicity.Nat Chem Biol 4:366–372.

Midorikawa R, Takei Y, Hirokawa N. 2006. KIF4 motor regulatesactivity-dependent neuronal survival by suppressing PARP-1enzymatic activity. Cell 125:371–383.

Miller PS, Da Silva HM, Smart TG. 2005. Molecular basis for zincpotentiation at strychnine-sensitive glycine receptors. J BiolChem 280:37877–37884.

Mills DA, Schmidt B, Hiser C, Westley E, Ferguson-Miller S. 2002.Membrane potential-controlled inhibition of cytochrome c oxidaseby zinc. J Biol Chem 277:14894–14901.

Min YK, Lee JE, Chung KC. 2007. Zinc induces cell death inimmortalized embryonic hippocampal cells via activation of Akt-GSK-3beta signaling. Exp Cell Res 313:312–321.

Mitchell CL, Barnes MI. 1993. Proconvulsant action of diethyldithio-carbamate in stimulation of the perforant path. NeurotoxicolTeratol 15:165–171.

Miyawaki T, Mashiko T, Ofengeim D, Flannery RJ, Noh KM,Fujisawa S, Bonanni L, Bennett MV, Zukin RS, Jonas EA. 2008.Ischemic preconditioning blocks BAD translocation. Bcl-xL cleav-age, and large channel activity in mitochondria of postischemichippocampal neurons. Proc Natl Acad Sci USA 105:4892–4897.

Mocchegiani E, Muzzioli M, Giacconi R. 2000. Zinc and immunore-sistance to infection in aging: New biological tools. Trends Phar-macol Sci 21:205–208.

Mocchegiani E, Giacconi R, Cipriano C, Muzzioli M, Fattoretti P,Bertoni-Freddari C, Isani G, Zambenedetti P, Zatta P. 2001. Zinc-bound metallothioneins as potential biological markers of ageing.Brain Res Bull 55:147–153.

Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M.2005. Brain, aging and neurodegeneration: Role of zinc ion avail-ability. Prog Neurobiol 75:367–390.

Moffatt P, Denizeau F. 1997. Metallothionein in physiological andphysiopathological processes. Drug Metab Rev 29:261–307.

Monnerie H, Le Roux PD. 2007. Reduced dendrite growth andaltered glutamic acid decarboxylase (GAD) 65- and 67-kDa iso-form protein expression from mouse cortical GABAergic neuronsfollowing excitotoxic injury in vitro. Exp Neurol 205:367–382.

Morton JD, Howell GA, Frederickson CJ. 1990. Effects of subcuta-neous injections of zinc chloride on seizures induced by noise andby kainic acid. Epilepsia 31:139–144.

Muller D, Toni N, Buchs PA. 2000. Spine changes associated withlong-term potentiation. Hippocampus 10:596–604.

Muller D, Nikonenko I, Jourdain P, Alberi S. 2002. LTP, memoryand structural plasticity. Curr Mol Med 2:605–611.

Mulligan VK, Kerman A, Ho S, Chakrabartty A. 2008. Denatura-tional stress induces formation of zinc-deficient monomers ofCu,Zn superoxide dismutase: Implications for pathogenesis inamyotrophic lateral sclerosis. J Mol Biol 383:424–436.

Multhaup G, Bush AI, Pollwein P, Masters CL. 1994. Interactionbetween the zinc (II) and the heparin binding site of the Alzhei-mer’s disease beta A4 amyloid precursor protein (APP). FEBSLett 355:151–154.

Multhaup G, Ruppert T, Schlicksupp A, Hesse L, Bill E, Pipkorn R,Masters CL, Beyreuther K. 1998. Copper-binding amyloid precur-sor protein undergoes a site-specific fragmentation in the reduc-tion of hydrogen peroxide. Biochemistry 37:7224–7230.

Nagano S, Satoh M, Sumi H, Fujimura H, Tohyama C, YanagiharaT, Sakoda S. 2001. Reduction of metallothioneins promotes thedisease expression of familial amyotrophic lateral sclerosis micein a dose-dependent manner. Eur J Neurosci 13:1363–1370.

Nakashima AS, Dyck RH. 2008. Enhanced plasticity in zincergic,cortical circuits after exposure to enriched environments. J Neuro-sci 28:13995–13999.

Nakashima AS, Dyck RH. 2009. Zinc and cortical plasticity. BrainRes Rev 59:347–373.

Nakashima AS, Oddo S, Laferla FM, Dyck RH. 2008. Experience-dependent regulation of vesicular zinc in male and female3xTg-AD mice. Neurobiol Aging [Epub ahead of print].

Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G.2005. Altered expression of GABA(A) and GABA(B) receptor subu-nit mRNAs in the hippocampus after kindling and electricallyinduced status epilepticus. Neuroscience 134:691–704.

Noh KM, Yokota H, Mashiko T, Castillo PE, Zukin RS, Bennett MV.2005. Blockade of calcium-permeable AMPA receptors protectshippocampal neurons against global ischemia-induced death. ProcNatl Acad Sci USA 102:12230–12235.

Nowak G, Schlegel-Zawadzka M. 1999. Alterations in serum andbrain trace element levels after antidepressant treatment. I. Zinc.Biol Trace Elem Res 67:85–92.

Nowak G, Szewczyk B, Wieronska JM, Branski P, Palucha A, PilcA, Sadlik K, Piekoszewski W. 2003. Antidepressant-like effects ofacute and chronic treatment with zinc in forced swim test and ol-factory bulbectomy model in rats. Brain Res Bull 61:159–164.

Nowak G, Legutko B, Szewczyk B, Papp M, Sanak M, Pilc A. 2004.Zinc treatment induces cortical brain-derived neurotrophic factorgene expression. Eur J Pharmacol 492:57–59.

Nowak G, Szewczyk B, Pilc A. 2005. Zinc and depression. Anupdate. Pharmacol Rep 57:713–718.

O’Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S,Klein PS. 2004. Glycogen synthase kinase-3beta haploinsuffi-ciency mimics the behavioral and molecular effects of lithium.J Neurosci 24:6791–6798.

Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. 2003a. Amy-loid deposition precedes tangle formation in a triple transgenicmodel of Alzheimer’s disease. Neurobiol Aging 24:1063–1070.


Synapse

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R,Metherate R, Mattson MP, Akbari Y, LaFerla FM. 2003b. Triple-transgenic model of Alzheimer’s disease with plaques and tangles:Intracellular Abeta and synaptic dysfunction. Neuron 39:409–421.

Oddo S, Caccamo A, Green KN, Liang K, Tran L, Chen Y, LeslieFM, LaFerla FM. 2005. Chronic nicotine administration exacer-bates tau pathology in a transgenic model of Alzheimer’s disease.Proc Natl Acad Sci USA 102:3046–3051.

Okazaki MM, Evenson DA, Nadler JV. 1995. Hippocampal mossyfiber sprouting and synapse formation after status epilepticus inrats: Visualization after retrograde transport of biocytin. J CompNeurol 352:515–534.

Opitz T, Grooms SY, Bennett MV, Zukin RS. 2000. Remodeling ofalpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid recep-tor subunit composition in hippocampal neurons after globalischemia. Proc Natl Acad Sci USA 97:13360–13365.

Palmiter RD, Findley SD. 1995. Cloning and functional characteri-zation of a mammalian zinc transporter that confers resistance tozinc. EMBO J 14:639–649.

Palmiter RD, Huang L. 2004. Efflux and compartmentalization ofzinc by members of the SLC30 family of solute carriers. PflugersArch 447:744–751.

Palmiter RD, Cole TB, Quaife CJ, Findley SD. 1996a. ZnT-3, a puta-tive transporter of zinc into synaptic vesicles. Proc Natl Acad SciUSA 93:14934–14939.

Palmiter RD, Cole TB, Findley SD. 1996b. ZnT-2, a mammalian pro-tein that confers resistance to zinc by facilitating vesicularsequestration. EMBO J 15:1784–1791.

Palmiter RD, Findley SD, Whitmore TE, Durnam DM. 1992. MT-III,a brain-specific member of the metallothionein gene family. ProcNatl Acad Sci USA 89:6333–6337.

Panayi AE, Spyrou NM, Iversen BS, White MA, Part P. 2002. Deter-mination of cadmium and zinc in Alzheimer’s brain tissue usinginductively coupled plasma mass spectrometry. J Neurol Sci195:1–10.

Pei Y, Zhao D, Huang J, Cao L. 1983. Zinc-induced seizures: A newexperimental model of epilepsy. Epilepsia 24:169–176.

Pellegrini-Giampietro DE, Gorter JA, Bennett MV, Zukin RS. 1997.The GluR2 (GluR-B) hypothesis: Ca(21)-permeable AMPA recep-tors in neurological disorders. Trends Neurosci 20:464–470.

Penkowa M, Nielsen H, Hidalgo J, Bernth N, Moos T. 1999. Distri-bution of metallothionein I 1 II and vesicular zinc in the develop-ing central nervous system: Correlative study in the rat. J CompNeurol 412:303–318.

Penkowa M, Giralt M, Camats J, Hidalgo J. 2002. Metallothionein112 protect the CNS during neuroglial degeneration induced by6-aminonicotinamide. J Comp Neurol 444:174–189.

Perez-Clausell J, Danscher G. 1985. Intravesicular localization ofzinc in rat telencephalic boutons. A histochemical study. BrainRes 337:91–98.

Perez-Clausell J, Danscher G. 1986. Release of zinc sulphide accu-mulations into synaptic clefts after in vivo injection of sodium sul-phide. Brain Res 362:358–361.

Perez-Clausell J, Frederickson CJ, Danscher G. 1989. Amygdaloidefferents through the stria terminalis in the rat give origin tozinc-containing boutons. J Comp Neurol 290:201–212.

Perry DK, Smyth MJ, Stennicke HR, Salvesen GS, Duriez P, PoirierGG, Hannun YA. 1997. Zinc is a potent inhibitor of the apoptoticprotease, caspase-3. A novel target for zinc in the inhibition of ap-optosis. J Biol Chem 272:18530–18533.

Porter BE, Zhang G, Celix J, Hsu FC, Raol YH, Telfeian A,Gallagher PR, Coulter DA, Brooks-Kayal AR. 2005. Heterogene-ous GABAA receptor subunit expression in pediatric epilepsypatients. Neurobiol Dis 18:484–491.

Powell SR. 2000. The antioxidant properties of zinc. J Nutr 130(5SSuppl):1447S–154S.

Prasad AS. 1995. Zinc: An overview. Nutrition 11(1 Suppl):93–99.Prasad AS. 2003. Zinc deficiency. BMJ 326:409–410.Prasad AS. 2008. Zinc in human health: Effect of zinc on immune

cells. Mol Med 14:353–357.Prasad AS, Bao B, Beck FW, Kucuk O, Sarkar FH. 2004. Antioxi-

dant effect of zinc in humans. Free Radic Biol Med 37:1182–1190.Pulsinelli WA, Brierley JB, Plum F. 1982. Temporal profile of

neuronal damage in a model of transient forebrain ischemia. AnnNeurol 11:491–498.

Puttaparthi K, Gitomer WL, Krishnan U, Son M, Rajendran B, ElliottJL. 2002. Disease progression in a transgenic model of familialamyotrophic lateral sclerosis is dependent on both neuronal andnon-neuronal zinc binding proteins. J Neurosci 22:8790–8796.

Qian J, Noebels JL. 2005 Visualization of transmitter release withzinc fluorescence detection at the mouse hippocampal mossy fibresynapse. J Physiol 566:747–758.

Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambro-wicz BP, Palmiter RD. 1994. Induction of a new metallothioneinisoform (MT-IV) occurs during differentiation of stratified squa-mous epithelia. Biochemistry 33:7250–7259.

Quinta-Ferreira ME, Matias CM. 2004. Hippocampal mossy fibercalcium transients are maintained during long-term potentiationand are inhibited by endogenous zinc. Brain Res 1004:52–60.

Quiroz JA, Gould TD, Manji HK. 2004. Molecular effects of lithium.Mol Interv 4:259–272.

Rassendren FA, Lory P, Pin JP, Nargeot J. 1990. Zinc has oppositeeffects on NMDA and non-NMDA receptors expressed in Xenopusoocytes. Neuron 4:733–740.

Redenti S, Chappell RL. 2005. Neuroimaging of zinc released bydepolarization of rat retinal cells. Vision Res 45:3520–3525.

Redenti S, Ripps H, Chappell RL. 2007. Zinc release at the synapticterminals of rod photoreceptors. Exp Eye Res 85:580–584.

Remy S, Spruston N. 2007. Dendritic spikes induce single-burstlong-term potentiation. Proc Natl Acad Sci USA 104:17192–17197.

Rink L, Gabriel P. 2000. Zinc and the immune system. Proc NutrSoc 59:541–552.

Rink L, Kirchner H. 2000. Zinc-altered immune function and cyto-kine production. J Nutr 130(5S Suppl):1407S–1411S.

Robbins AH, Stout CD. 1991. X-ray structure of metallothionein.Methods Enzymol 205:485–502.

Roberts BR, Tainer JA, Getzoff ED, Malencik DA, Anderson SR,Bomben VC, Meyers KR, Karplus PA, Beckman JS. 2007. Struc-tural characterization of zinc-deficient human superoxide dismu-tase and implications for ALS. J Mol Biol 373:877–890.

Roe JA, Wiedau-Pazos M, Moy VN, Goto JJ, Gralla EB, ValentineJS. 2002. In vivo peroxidative activity of FALS-mutant humanCuZnSODs expressed in yeast. Free Radic Biol Med 32: 169–174.

Rosa AO, Lin J, Calixto JB, Santos AR, Rodrigues AL. 2003.Involvement of NMDA receptors and L-arginine-nitric oxide path-way in the antidepressant-like effects of zinc in mice. Behav BrainRes 144:87–93.

Rosati AM, Traversa U. 1999. Mechanisms of inhibitory effects ofzinc and cadmium ions on agonist binding to adenosine A1 recep-tors in rat brain. Biochem Pharmacol 58:623–632.

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, HentatiA, Donaldson D, Goto J, O’Regan JP, Deng HX, Rahmani Z, Kri-zus A, McKenna-Yasek D, Cayabyab A, Gaston SM, Berger R,Tanzi RE, Halperin JT, Herzfeldt B, Van den Bergh R, Hung W-Y,Bird T, Deng G, Mulder DW, Smyth C, Laing NG, Soriano E, Peri-cak-Vance MA, Haines J, Rouleau GA, Gusella JS, Horvitz HR,Brown Jr RH. 1993. Mutations in Cu/Zn superoxide dismutasegene are associated with familial amyotrophic lateral sclerosis.Nature 362:59–62.

Ross GM, Shamovsky IL, Lawrance G, Solc M, Dostaler SM, JimmoSL, Weaver DF, Riopelle RJ. 1997. Zinc alters conformation andinhibits biological activities of nerve growth factor and relatedneurotrophins. Nat Med 3:872–878.

Rubio ME, Juiz JM. 1998. Chemical anatomy of excitatory endingsin the dorsal cochlear nucleus of the rat: Differential synaptic dis-tribution of aspartate aminotransferase, glutamate, and vesicularzinc. J Comp Neurol 399:341–358.

Rulon LL, Robertson JD, Lovell MA, Deibel MA, Ehmann WD,Markesber WR. 2000. Serum zinc levels and Alzheimer’s disease.Biol Trace Elem Res 75:79–85.

Saito T, Takahashi K, Nakagawa N, Hosokawa T, Kurasaki M,Yamanoshita O, Yamamoto Y, Sasaki H, Nagashima K, Fujita H.2000. Deficiencies of hippocampal Zn and ZnT3 accelerate brainaging of Rat. Biochem Biophys Res Commun 279:505–511.

Samudralwar DL, Diprete CC, Ni BF, Ehmann WD, MarkesberyWR. 1995. Elemental imbalances in the olfactory pathway in Alz-heimer’s disease. J Neurol Sci 130:139–145.

Sandstead HH. 2003. Zinc is essential for brain development andfunction. J Trace Elem Exp Med 16:165–173.

Sandstead HH, Frederickson CJ, Penland JG. 2000. History of zincas related to brain function. J Nutr 130(2S Suppl):496S–502S.

Schetz JA, Sibley DR. 1997. Zinc allosterically modulates antagonistbinding to cloned D1 and D2 dopamine receptors. J Neurochem68:1990–1997.

Schetz JA, Chu A, Sibley DR. 1999. Zinc modulates antagonistinteractions with D2-like dopamine receptors through distinctmolecular mechanisms. J Pharmacol Exp Ther 289:956–964.

Sekler I, Moran A, Hershfinkel M, Dori A, Margulis A, BirenzweigN, Nitzan Y, Silverman WF. 2002. Distribution of the zinc trans-porter ZnT-1 in comparison with chelatable zinc in the mousebrain. J Comp Neurol 447:201–209.

Sekler I, Sensi SL, Hershfinkel M, Silverman WF. 2007. Mechanismand regulation of cellular zinc transport. Mol Med 13:337–343.


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Sensi SL, Jeng JM. 2004. Rethinking the excitotoxic ionic milieu:The emerging role of Zn(21) in ischemic neuronal injury. CurrMol Med 4:87–111.

Sensi SL, Yin HZ, Carriedo SG, Rao SS, Weiss JH. 1999. Preferen-tial Zn21 influx through Ca21-permeable AMPA/kainate chan-nels triggers prolonged mitochondrial superoxide production. ProcNatl Acad Sci USA 96:2414–2419.

Sensi SL, Yin HZ, Weiss JH. 2000. AMPA/kainate receptor-triggeredZn21 entry into cortical neurons induces mitochondrial Zn21uptake and persistent mitochondrial dysfunction. Eur J Neurosci12:3813–3818.

Sensi SL, Ton-That D, Weiss JH. 2002. Mitochondrial sequestrationand Ca(21)-dependent release of cytosolic Zn(21) loads in corticalneurons. Neurobiol Dis 10:100–108.

Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR, KaczmarekLK, Weiss JH. 2003. Modulation of mitochondrial function by en-dogenous Zn21 pools. Proc Natl Acad Sci USA 100:6157–6162.

Sensi SL, Rockabrand RL, Sekler I. 2007. Zinc homeostasis andbrain injury. In: Malva J, Rego AC, Oliveira C, Cunha R, editors.Interaction between neurons and glia in aging and disease. NewYork: Springer. p 221–244.

Sensi SL, Rapposelli IG, Frazzini V, Mascetra N. 2008. Altered oxi-dant-mediated intraneuronal zinc mobilization in a triple transgenicmouse model of Alzheimer’s disease. Exp Gerontol 43:488–492.

Seve M, Chimienti F, Devergnas S, Favier A. 2004. In silico identifi-cation and expression of SLC30 family genes: An expressedsequence tag data mining strategy for the characterization of zinctransporters’ tissue expression. BMC Genomics 5:32.

Sheline CT, Behrens MM, Choi DW. 2000. Zinc-induced cortical neu-ronal death: Contribution of energy failure attributable to loss ofNAD(1) and inhibition of glycolysis. J Neurosci 20:3139–3146.

Shigihara S, Ikui A, Shigihara J, Tomita H, Okano M. 1987. Elec-tron microscopy of the olfactory epithelium in zinc deficient rats.Ann N Y Acad Sci 510:606–609.

Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. 2002.Brain-derived neurotrophic factor produces antidepressant effectsin behavioral models of depression. J Neurosci 22:3251–3261.

Sillevis Smitt PA, Blaauwgeers HG, Troost D, de Jong JM. 1992. Metal-lothionein immunoreactivity is increased in the spinal cord of patientswith amyotrophic lateral sclerosis. Neurosci Lett 144:107–110.

Sillevis Smitt PA, Mulder TP, Verspaget HW, Blaauwgeers HG,Troost D, de Jong JM. 1994. Metallothionein in amyotrophiclateral sclerosis. Bio Signals 3:193–197.

Sindreu CB, Varoqui H, Erickson JD, Perez-Clausell J. 2003. Boutonscontaining vesicular zinc define a subpopulation of synapses withlow AMPAR content in rat hippocampus. Cereb Cortex 13:823–829.

Singh RJ, Karoui H, Gunther MR, Beckman JS, Mason RP, Kalya-naraman B. 1998. Reexamination of the mechanism of hydroxylradical adducts formed from the reaction between familial amyo-trophic lateral sclerosis-associated Cu, Zn superoxide dismutasemutants and H2O2. Proc Natl Acad Sci USA 95:6675–6680.

Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM. 1997. Antidepres-sant-like effect of brain-derived neurotrophic factor (BDNF). Phar-macol Biochem Behav 56:131–137.

Skolnick P, Legutko B, Li X, Bymaster FP. 2001. Current perspec-tives on the development of non-biogenic amine-based antidepres-sants. Pharmacol Res 43:411–423.

Slomianka L. 1992. Neurons of origin of zinc-containing pathwaysand the distribution of zinc-containing boutons in the hippocam-pal region of the rat. Neuroscience 48:325–352.

Slomianka L, Danscher G, Frederickson CJ. 1990. Labeling of theneurons of origin of zinc-containing pathways by intraperitonealinjections of sodium selenite. Neuroscience 38:843–854.

Sloviter RS. 1985. A selective loss of hippocampal mossy fiber Timmstain accompanies granule cell seizure activity induced by perfo-rant path stimulation. Brain Res 330:150–153.

Smart TG, Xie X, Krishek BJ. 1994. Modulation of inhibitory andexcitatory amino acid receptor ion channels by zinc. Prog Neuro-biol 42:393–441.

Smart TG, Hosie AM, Miller PS. 2004. Zn21 ions: Modulators of exci-tatory and inhibitory synaptic activity. Neuroscientist 10:432–442.

Smith AP, Lee NM. 2007. Role of zinc in ALS. Amyotroph LateralScler 8:131–143.

Sowa-Kucma M, Legutko B, Szewczyk B, Novak K, Znojek P, Pole-szak E, Papp M, Pilc A, Nowak G. 2008. Antidepressant-likeactivity of zinc: Further behavioral and molecular evidence.J Neural Transm 115:1621–1628.

Spahl DU, Berendji-Grun D, Suschek CV, Kolb-Bachofen V, KronckeKD. 2003. Regulation of zinc homeostasis by inducible NO syn-thase-derived NO: Nuclear metallothionein translocation and intra-nuclear Zn21 release. Proc Natl Acad Sci USA 100:13952–13957.

Sperk G. 2007. Changes in GABAA receptors in status epilepticus.Epilepsia 48(Suppl 8):11–13.

Sterman MB, Shouse MN, Fairchild MD. 1988. Zinc and seizuremechanisms. In: Morley JE, Sterman MB, Walsh JH, editors.Nutritional modulation of neural function. San Diego: AcademicPress. p 307–319.

Stoltenberg M, Bush AI, Bach G, Smidt K, Larsen A, Rungby J, LundS, Doering P, Danscher G. 2007. Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxi-cally enlarged with dietary zinc deficiency. Neuroscience 150:357–369.

Suh SW, Jensen KB, Jensen MS, Silva DS, Kesslak PJ, Danscher G,Frederickson CJ. 2000. Histochemically-reactive zinc in amyloidplaques, angiopathy, and degenerating neurons of Alzheimer’sdiseased brains. Brain Res 852:274–278.

Suh SW, Jo SM, Vajda Z, Danscher G. 2001. Adrenalectomy causesloss of zinc ions in zinc-enriched (ZEN) terminals and decreasesseizure-induced neuronal death. Brain Res 895:25–32.

Sunderman FW Jr. 1995. The influence of zinc on apoptosis. AnnClin Lab Sci 25:134–142.

Suzuki J, Kasamo K, Ishida N, Murashima YL. 1991. Initiation,propagation and generalization of paroxysmal discharges in anepileptic mutant animal. Jpn J Psychiatry Neurol 45:271–274.

Swaminath G, Steenhuis J, Kobilka B, Lee TW. 2002. Allosteric modula-tion of beta2-adrenergic receptor by Zn(21). Mol Pharmacol 61:65–72.

Takeda A. 2000. Movement of zinc and its functional significance inthe brain. Brain Res Brain Res Rev 34:137–148.

Takeda A. 2001. Zinc homeostasis and functions of zinc in the brain.Biometals 14:343–351.

Takeda A, Hanajima T, Ijiro H, Ishige A, Iizuka S, Okada S, Oku N.1999. Release of zinc from the brain of El (epilepsy) mice duringseizure induction. Brain Res 828:174–178.

Takeda A, Hirate M, Tamano H, Oku N. 2003. Zinc movement in thebrain under kainate-induced seizures. Epilepsy Res 54:123–129.

Takeda A, Fuke S, Ando M, Oku N. 2009. Positive modulation oflong-term potentiation at hippocampal CA1 synapses by lowmicromolar concentrations of zinc. Neuroscience 158:585–591

Tapiero H, Tew KD. 2003. Trace elements in human physiology andpathology: Zinc and metallothioneins. Biomed Pharmacother57:399–411.

Tassabehji NM, Corniola RS, Alshingiti A, Levenson CW. 2008. Zincdeficiency induces depression-like symptoms in adult rats. PhysiolBehav 95:365–369.

Telford WG, Fraker PJ. 1995. Preferential induction of apoptosis inmouse CD41CD81 alpha beta TCRloCD3 epsilon lo thymocytesby zinc. J Cell Physiol 164:259–270.

Thompson CE, Markesbery WR, Ehmann WD, Mao YX, Vance DE.1988. Regional brain trace element studies in Alzheimer’s disease.Neurotoxicology 9:1–7.

Todorova MT, Burwell TJ, Seyfried TN. 1999. Environmental risk fac-tors for multifactorial epilepsy in EL mice. Epilepsia 40:1697–1707.

Tønder N, Johansen FF, Frederickson CJ, Zimmer J, Diemer NH.1990. Possible role of zinc in the selective degeneration of dentatehilar neurons after cerebral ischemia in the adult rat. NeurosciLett 109:247–252.

Truong-Tran AQ, Ho LH, Chai F, Zalewski PD. 2000. Cellular zincfluxes and the regulation of apoptosis/gene-directed cell death.J Nutr 130(5S Suppl):1459S–1466S.

Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD. 2001. The roleof zinc in caspase activation and apoptotic cell death. Biometals14:315–330.

Truong-Tran AQ, Ruffin RE, Foster PS, Koskinen AM, Coyle P, Phil-cox JC, Rofe AM, Zalewski PD. 2002. Altered zinc homeostasisand caspase-3 activity in murine allergic airway inflammation.Am J Respir Cell Mol Biol 27:286–296.

Tsuda M, Imaizumi K, Katayama T, Kitagawa K, Wanaka A,Tohyama M, Takagi T. 1997. Expression of zinc transporter gene.ZnT-1, is induced after transient forebrain ischemia in the gerbil.J Neurosci 17:6678–6684.

Tsuji S, Kobayashi H, Uchida Y, Ihara Y, Miyatake T. 1992. Molecu-lar cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer’s disease. EMBO J 11:4843–4850.

Uchibori M, Saito K, Yokoyama S, Sakamoto Y, Suzuki H, Tsuji T,Suzuki K. 2002. Foci identification of spike discharges in theEEGs of sleeping El mice based on the electric field model andwavelet decomposition of multi monopolar derivations. J NeurosciMethods 117:51–63.

Uchida Y. 1994. Growth-inhibitory factor, metallothionein-like pro-tein, and neurodegenerative diseases. Biol Signals 3:211–215.

Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M. 1991. Thegrowth inhibitory factor that is deficient in the Alzheimer’s dis-ease brain is a 68 amino acid metallothionein-like protein. Neuron7:337–347.


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Ueno S, Tsukamoto M, Hirano T, Kikuchi K, Yamada MK, NishiyamaN, Nagano T, Matsuki N, Ikegaya Y. 2002. Mossy fiber Zn21spillover modulates heterosynaptic N-methyl-D-aspartate receptoractivity in hippocampal CA3 circuits. J Cell Biol 158:215–220.

Ugarte M, Osborne NN. 2001. Zinc in the retina. Progr Neurobiol64:219–249.

Uki M, Narahashi T. 1996. Modulation of serotonin-induced cur-rents by metals in mouse neuroblastoma cells. Arch Toxicol70:652–660.

Vaidya VA, Siuciak JA, Du F, Duman RS. 1999. Hippocampal mossyfiber sprouting induced by chronic electroconvulsive seizures.Neuroscience 89:157–166.

Valente T, Auladell C. 2002. Developmental expression of ZnT3 inmouse brain: Correlation between the vesicular zinc transporterprotein and chelatable vesicular zinc (CVZ) cells. Glial and neuro-nal CVZ cells interact. Mol Cell Neurosci 21:189–204.

Valente T, Auladell C, Perez-Clausell J. 2002. Postnatal develop-ment of zinc-rich terminal fields in the brain of the rat. Exp Neu-rol 174:215–229.

Vallee BL, Auld DS. 1993. New perspective on zinc biochemistry: Coca-talytic sites in multi-zinc enzymes. Biochemistry 32:6493–6500.

Vallee BL, Falchuk KH. 1993. The biochemical basis of zinc physiol-ogy. Physiol Rev 73:79–118.

Vasak M. 2005. Advances in metallothionein structure and func-tions. J Trace Elem Med Biol 19:13–17.

Vasak M, Hasler DW. 2000. Metallothioneins-new structural andfunctional insights. Curr Opin Chem Biol 4:177–183.

Vela JM, Hidalgo J, Gonzalez B, Castellano B. 1997. Induction ofmetallothionein in astrocytes and microglia in the spinal cordfrom the myelin-deficient jimpy mouse. Brain Res 767:345–355.

Vincent SR, Semba K. 1989. A heavy metal marker of the develop-ing striatal mosaic. Brain Res Dev Brain Res 45:155–159.

Vogt K, Mellor J, Tong G, Nicoll R. 2000. The actions of synapticallyreleased zinc at hippocampal mossy fiber synapses. Neuron26:187–196.

Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. 2000.Decreased glutamic acid decarboxylase67 messenger RNA expressionin a subset of prefrontal cortical gamma-aminobutyric acid neuronsin subjects with schizophrenia. Arch Gen Psychiatry 57:237–245.

Vonk WI, Klomp LW. 2008. Role of transition metals in the pathoge-nesis of amyotrophic lateral sclerosis. Biochem Soc Trans 36(Part6):1322–1328.

Vorobjev VS, Sharonova IN, Sergeeva OA, Haas HL. 2003. Modula-tion of ATP-induced currents by zinc in acutely isolated hypo-thalamic neurons of the rat. Br J Pharmacol 139:919–926.

Wang Y-X, Quastel DMJ. 1990. Multiple actions of zinc on transmit-ter release at mouse end-plates. Eur J Physiol 415:582–587.

Watjen W, Benters J, Haase H, Schwede F, Jastorff B, BeyersmannD. 2001. Zn2+ and Cd2+ increase the cyclic GMP level in PC12cells by inhibition of the cyclic nucleotide phosphodiesterase. Toxi-cology 157:167–175.

Watjen W, Haase H, Biagioli M, Beyersmann D. 2002. Induction ofapoptosis in mammalian cells by cadmium and zinc. EnvironHealth Perspect 110(Suppl 5):865–867.

Weiss JH, Sensi SL. 2000. Ca21-Zn21 permeable AMPA or kainatereceptors: Possible key factors in selective neurodegeneration.Trends Neurosci 23:365–371.

Weiss JH, Koh JY, Christine CW, Choi DW. 1989. Zinc and LTP.Nature 338:212.

Weiss JH, Hartley DM, Koh JY, Choi DW. 1993. AMPA receptoractivation potentiates zinc neurotoxicity. Neuron 10:43–49.

Wengenack TM, Whelan S, Curran GL, Duff KE, Poduslo JF. 2000.Quantitative histological analysis of amyloid deposition in Alzhei-mer’s double transgenic mouse brain. Neuroscience 101:939–944.

Wenzel HJ, Cole TB, Born DE, Schwartzkroin PA, Palmiter RD.1997. Ultrastructural localization of zinc transporter-3 (ZnT-3) to

synaptic vesicle membranes within mossy fiber boutons in thehippocampus of mouse and monkey. Proc Natl Acad Sci USA94:12676–12681.

West AK, Stallings R, Hildebrand CE, Chiu R, Karin M, RichardsRI. 1990. Human metallothionein genes: Structure of the func-tional locus at 16q13. Genomics 8:513–518.

White G, Gurley DA. 1995. Alpha subunits influence Zn block ofgamma 2 containing GABAA receptor currents. Neuroreport6:461–464.

Wildman SS, King BF, Burnstock G. 1998. Zn21 modulation ofATP-responses at recombinant P2X2 receptors and its dependenceon extracellular pH. Br J Pharmacol 123:1214–1220.

Wildman SS, Brown SG, Rahman M, Noel CA, Churchill L,Burnstock G, Unwin RJ, King BF. 2002. Sensitization by extracel-lular Ca(21) of rat P2X(5) receptor and its pharmacological prop-erties compared with rat P2X(1). Mol Pharmacol 62:957–966.

Wildman SS, Unwin RJ, King BF. 2003. Extended pharmacologicalprofiles of rat P2Y2 and rat P2Y4 receptors and their sensitivity toextracellular H1 and Zn21 ions. Br J Pharmacol 140:1177–1186.

Williamson A, Spencer D. 1995. Zinc reduces dentate granule cellhyperexcitability in epileptic humans. Neuroreport 6:1562–1564.

Williams RJ, Spencer JP, Goni FM, Rice-Evans CA. 2004. Zinc-histi-dine complex protects cultured cortical neurons against oxidativestress-induced damage. Neurosci Lett 371:106–110.

Woo TU, Walsh JP, Benes FM. 2004. Density of glutamic acid decar-boxylase 67 messenger RNA-containing neurons that express theN-methyl-D-aspartate receptor subunit NR2A in the anteriorcingulate cortex in schizophrenia and bipolar disorder. Arch GenPsychiatry 61:649–657.

Woo TU, Shrestha K, Lamb D, Minns MM, Benes FM. 2008. N-methyl-D-aspartate receptor and calbindin-containing neurons inthe anterior cingulate cortex in schizophrenia and bipolar disor-der. Biol Psychiatry 64:803–809.

Xie X, Smart TG. 1991. A physiological role for endogenous zinc in rathippocampal synaptic neurotransmission. Nature 349:521–524.

Xie X, Smart TG. 1994. Modulation of long-term potentiation in rathippocampal pyramidal neurons by zinc. Pflugers Arch 427:481–486.

Xiong K, Peoples RW, Montgomery JP, Chiang Y, Stewart RR, WeightFF, Li C. 1999. Differential modulation by copper and zinc of P2X2and P2X4 receptor function. J Neurophysiol 81:2088–2094.

Yin HZ, Sensi SL, Ogoshi F, Weiss JH. 2002. Blockade of Ca21-per-meable AMPA/kainate channels decreases oxygen-glucose depriva-tion-induced Zn21 accumulation and neuronal loss in hippocam-pal pyramidal neurons. J Neurosci 22:1273–1279.

Yu WH, Lukiw WJ, Bergeron C, Niznik HB, Fraser PE. 2001.Metallothionein III is reduced in Alzheimer’s disease. Brain Res894:37–45.

Zago MP, Oteiza PI. 2001. The antioxidant properties of zinc: Interac-tions with iron and antioxidants. Free Radic Biol Med 31:266–274.

Zalewski PD, Forbes IJ, Betts WH. 1993. Correlation of apoptosiswith change in intracellular labile Zn(II) using zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetic acid], a new specificfluorescent probe for Zn(II). Biochem J 296(Part 2):403–408.

Zhang N, Wei W, Mody I, Houser CR. 2007. Altered localization ofGABA(A) receptor subunits on dentate granule cell dendritesinfluences tonic and phasic inhibition in a mouse model of epi-lepsy. J Neurosci 27:7520–7531.

Zhang LH, Wang X, Stoltenberg M, Danscher G, Huang L, WangZY. 2008. Abundant expression of zinc transporters in the amyloidplaques of Alzheimer’s disease brain. Brain Res Bull 77:55–60.

Zheng H, Berman NE, Klaassen CD. 1995. Chemical modulation ofmetallothionein I and III mRNA in mouse brain. Neurochem Int27:43–58.

Zirpel L, Parks TN. 2001. Zinc inhibition of group I mGluR-medi-ated calcium homeostasis in auditory neurons. J Assoc Res Oto-laryngol 2:180–187.


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zinc: the brain's dark horse

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