Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the
            <i>ZnT</i>
            <i>3</i>
            gene

Cole, Toby B.; Wenzel, H. Jürgen; Kafer, Kathy E.; Schwartzkroin, Philip A.; Palmiter, Richard D.

doi:10.1073/pnas.96.4.1716

Cited by 503 publications

(475 citation statements)

References 36 publications

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“…In our cultured neurons, both fluorescent signals are mobilized in the presence of ␣-latrotoxin, arguing in favor of their presence in synaptic vesicles. On the other hand, we estimate that most of the zinquin fluorescence detected by us is due to ZnT3 because ZnT3 Ϫ/Ϫ mice completely lack ionic zinc in their hippocampus (Cole et al, 1999). However, the contribution of other zinc transporters expressed in brain, although likely to be minor (Huang, 1997;Huang et al, 2002;Kambe et al, 2002), cannot be ruled out yet.…”

Section: Discussionmentioning

confidence: 74%

“…Zinquin, a Zinc-sensitive Probe, Reveals Heterogeneity in Neuronal Vesicular Stores To monitor in vivo the function of ZnT3 in hippocampal neurons, we used as an indicator the vesicular ionic zinc stores. The rationale for selecting ionic zinc as a tool was based in the following observations: 1) disruption of the ZnT3 gene in mouse leads to a disappearance of all detectable ionic zinc in neurons (Cole et al, 1999), indicating that ZnT3 is the main vesicular ionic zinc transport mechanism in brain; and 2) AP-3-deficient neurons do not store vesicular ionic zinc (Kantheti et al, 1998) because of a lack of ZnT3 in their SV (Kantheti et al, 1998) (Figure 7). Because SV uptake of ionic zinc increases intravesicular pH (Goncalves et al, 1999), we hypothesized that if vesicles differ in their ZnT3 content or function, then differences in the vesicular pH should be detectable on single terminals.…”

Section: Znt3 and Synaptophysin Are Enriched In Different Populationsmentioning

confidence: 99%

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The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

112

178

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Synaptic vesicles (SV) are generated by two different mechanisms, one AP-2 dependent and one AP-3 dependent. It has been uncertain, however, whether these mechanisms generate SV that differ in molecular composition. We explored this hypothesis by analyzing the targeting of ZnT3 and synaptophysin both to PC12 synaptic-like microvesicles (SLMV) as well as SV isolated from wild-type and AP-3-deficient mocha brains. ZnT3 cytosolic tail interacted selectively with AP-3 in cell-free assays. Accordingly, pharmacological disruption of either AP-2-or AP-3-dependent SLMV biogenesis preferentially reduced synaptophysin or ZnT3 targeting, respectively; suggesting that these antigens were concentrated in different vesicles. As predicted, immuno-isolated SLMV revealed that ZnT3 and synaptophysin were enriched in different vesicle populations. Likewise, morphological and biochemical analyses in hippocampal neurons indicated that these two antigens were also present in distinct but overlapping domains. ZnT3 SV content was reduced in AP-3-deficient neurons, but synaptophysin was not altered in the AP-3 null background. Our evidence indicates that neuroendocrine cells assemble molecularly heterogeneous SV and suggests that this diversity could contribute to the functional variety of synapses. INTRODUCTIONThe molecular diversity in total brain synaptic vesicle (SV) composition is generally presumed to result from differential expression of synaptic vesicle membrane proteins in different brain regions. However, the possibility that synaptic vesicles differ in composition because of different biogenesis mechanisms has not been explored. Different vesiculation pathways could result in molecularly diverse synaptic vesicles. Vesiculation mechanisms are known to produce distinct cargo carriers from a population of donor membranes (Bonifacino and Dell'Angelica, 1999;Springer et al., 1999;Boehm and Bonifacino, 2001). This process is achieved by adaptor complexes that recognize and concentrate specific membrane proteins in the donor membranes (Bonifacino and Dell 'Angelica, 1999;Kirchhausen, 1999). PC12 cells have been shown to possess two such adaptor-dependent pathways for the assembly of synaptic vesicles, also known as synaptic-like microvesicles (SLMV) (Shi et al., 1998;de Wit et al., 1999;Jarousse and Kelly, 2001). In one pathway, SLMV are generated from the plasma membrane by a vesiculation mechanism that requires the adaptor AP-2, clathrin, and the GTPase dynamin (Shi et al., 1998). In the second pathway, SLMV are generated from endosomes by the adaptor complex AP-3 (Faundez et al., 1998;Blumstein et al., 2001) and the GTPase ARF1 (Faundez et al., 1997). In contrast to the plasma membrane pathway, the endosomederived mechanism is highly sensitive to brefeldin A (BFA) (Shi et al., 1998).Phenotypes observed in the AP-3-deficient mocha mouse are consistent with a role for the AP-3-dependent, endosome-derived pathway in neurons (Kantheti et al., 1998). The mocha mossy fibers are devoid of both the synaptic vesiclespecific zinc transpor...

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Section: Discussionmentioning

confidence: 74%

Section: Znt3 and Synaptophysin Are Enriched In Different Populationsmentioning

confidence: 99%

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Salazar

Love

Werner

et al. 2004

MBoC

112

178

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“…Only a fraction of neurons in fear conditioning pathways expresses ZnT-3 transporter, a specific marker for zinc-containing neurons (4,21,30). Furthermore, in the present study both Zn 2ϩ and ZnT-3 were detected in the LA and in the temporal area 3 of the auditory cortex, but not in the medial division of the medial geniculate nucleus͞ posterior intralaminar nucleus region of the auditory thalamus, afferent areas that deliver to the LA the auditory CS information during fear conditioning (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…RNA in situ hybridization was performed as described previously (31). Timm staining was performed by using a modification of a previously published protocol (30,32). Briefly, a 1-month-old rat (125 g body weight) was anesthetized by 3.5 ml of 1.25% Avertin solution i.p.…”

Section: Methodsmentioning

confidence: 99%

Synaptically released zinc gates long-term potentiation in fear conditioning pathways

Kodirov

Takizawa²,

Joseph³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The functional role of releasable Zn 2؉ in the central nervous system remains unknown. Here we show that zinc transporter 3 (ZnT-3), which maintains a high concentration of Zn 2؉ in synaptic vesicles and serves as a marker for zinc-containing neurons, is enriched in the lateral nucleus of the amygdala and in the temporal area 3 of the auditory cortex, an area that conveys information about the auditory conditioned stimulus to the lateral nucleus of the amygdala, but not in other conditioned stimulus areas located in the auditory thalamus. Using whole-cell recordings from amygdala slices, we demonstrated that activity-dependent release of chelatable Zn 2؉ is required for the induction of spike timing-dependent long-term potentiation in cortical input to the amygdala implicated in fear learning. Our data indicate that synaptically released Zn 2؉ enables long-term potentiation at the cortico-amygdala synapses by depressing feed-forward GABAergic inhibition of principal neurons. This regulatory mechanism, implicating pathway-dependent release of Zn 2؉ , may serve an essential control function in assuring spatial specificity of long-lasting synaptic modifications in the neural circuit of a learned behavior.amygdala ͉ synapse ͉ synaptic plasticity ͉ glutamate ͉ GABA L ong-term potentiation (LTP) in afferent inputs to the amygdala is recruited during fear conditioning and used for retention of fear memory (1-5). A subset of glutamatergic neurons in fear conditioning pathways, including pyramidal neurons in the lateral nucleus of the amygdala (LA) where conditioned stimuli (CS) and unconditioned stimuli converge during fear learning (6-9), is enriched in zinc (Zn 2ϩ ) (4). Zn 2ϩ is found to be in a high concentration in synaptic vesicles at various synapses and to be colocalized with the neurotransmitters glutamate or GABA (10,11). Previous studies have demonstrated that this vesicular Zn 2ϩ can be released in a Ca 2ϩ -dependent manner in different regions of the brain, including the hippocampus, cortex, and amygdala, in response to synaptic stimulation at both glutamatergic and GABAergic synapses (11)(12)(13)(14)(15)(16)(17)(18)(19). This set of findings suggested to us the possibility that vesicular zinc may have a role in synaptic plasticity in the neural circuitry of fear learning.Zn 2ϩ has been implicated in a variety of neuronal functions in the mammalian brain both as a paracrine and as an autocrine mediator (20). However, despite intensive efforts the functional role of releasable zinc in synaptic transmission and plasticity remained elusive (10, 20). Here we report that chelatable zinc, released during synaptic activation, is critically involved in control of LTP in the cortico-amygdala pathway, which conveys auditory information about the CS to the amygdala during fear conditioning. We find that zinc acts by suppressing feed-forward inhibition of projection neurons by local circuit interneurons. The pathway-specific expression of zinc-containing cells suggests that this regulatory mechanism may define the spat...

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“…However, the pleiotropic neurological defects observed in mocha alleles are not fully recapitulated by a ZnT3-null mutant mouse (12,13). This suggests that AP-3 could regulate the targeting of as-yet-unidentified proteins to synaptic vesicles that determine their luminal composition.…”

mentioning

confidence: 93%

AP-3-dependent Mechanisms Control the Targeting of a Chloride Channel (ClC-3) in Neuronal and Non-neuronal Cells

Salazar¹,

Love²,

Styers³

et al. 2004

Journal of Biological Chemistry

109

133

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Adaptor protein (AP)-2 and AP-3-dependent mechanisms control the sorting of membrane proteins into synaptic vesicles. Mouse models deficient in AP-3, mocha, develop a neurological phenotype of which the central feature is an alteration of the luminal synaptic vesicle composition. This is caused by a severe reduction of vesicular levels of the zinc transporter 3 (ZnT3). It is presently unknown whether this mocha defect is restricted to ZnT3 or encompasses other synaptic vesicle proteins capable of modifying synaptic vesicle contents, such as transporters or channels. In this study, we identified a chloride channel, ClC-3, whose level in synaptic vesicles and hippocampal mossy fiber terminals was reduced in the context of the mocha AP-3 deficiency. In PC-12 cells, ClC-3 was present in transferrin receptorpositive endosomes, where it was targeted to synapticlike microvesicles (SLMV) by a mechanism sensitive to brefeldin A, a signature of the AP-3-dependent route of SLMV biogenesis. ClC-3 was packed in SLMV along with the AP-3-targeted synaptic vesicle protein ZnT3. Co-segregation of ClC-3 and ZnT3 to common intracellular compartments was functionally significant as revealed by increased vesicular zinc transport with increased ClC3 expression. Our work has identified a synaptic vesicle protein in which trafficking to synaptic vesicles is regulated by AP-3. In addition, our findings indicate that ClC-3 and ZnT3 reside in a common vesicle population where they functionally interact to determine vesicle luminal composition.

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Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT 3 gene

Cited by 503 publications

References 36 publications

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

The Zinc Transporter ZnT3 Interacts with AP-3 and It Is Preferentially Targeted to a Distinct Synaptic Vesicle Subpopulation

Synaptically released zinc gates long-term potentiation in fear conditioning pathways

AP-3-dependent Mechanisms Control the Targeting of a Chloride Channel (ClC-3) in Neuronal and Non-neuronal Cells

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