 |
 Previous Article | Next Article 
The Journal of Neuroscience, 2000, 20:RC79:1-5
RAPID COMMUNICATION
Accumulation of Zinc in Degenerating Hippocampal Neurons of
ZnT3-Null Mice after Seizures: Evidence against Synaptic Vesicle
Origin
Joo-Yong
Lee1,
Toby B.
Cole2,
Richard D.
Palmiter2, and
Jae-Young
Koh1
1 National Creative Research Initiative Center for the
Study of CNS Zinc, University of Ulsan College of Medicine, Seoul
138-736, Korea, and 2 Howard Hughes Medical Institute,
Department of Biochemistry, University of Washington, Seattle,
Washington 98195
 |
ABSTRACT |
In several brain injury models, zinc accumulates in degenerating
neuronal somata. Suggesting that such zinc accumulation may play a
causal role in neurodegeneration, zinc chelation attenuates neuronal
death. Because histochemically reactive zinc is present in and released
from synaptic vesicles of glutamatergic neurons in the forebrain, it
was proposed that zinc translocation from presynaptic terminals to
postsynaptic neurons may be the mechanism of toxic zinc accumulation.
To test this hypothesis, kainate seizure-induced neuronal death was
examined in zinc transporter 3 gene (ZnT3)-null mice, a
strain that completely lacks histochemically reactive zinc in synaptic
vesicles. Intraperitoneal injection of kainate induced seizures to a
similar degree in wild type and ZnT3-null mice. Staining
of hippocampal sections with a zinc-specific fluorescent dye,
N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulfonamide,
revealed that zinc accumulated in degenerating CA1 and CA3 neurons
in both groups, indicating that zinc originated from sources other than synaptic vesicles. Injection of CaEDTA into the cerebral ventricle almost completely blocked zinc accumulation in ZnT3-null
mice, suggesting that increases in extracellular zinc concentrations may be a critical event for zinc accumulation. Arguing against the
possibility that zinc accumulation results from nonspecific breakdown
of zinc-containing proteins, injection of kainate into the cerebellum
did not induce zinc accumulation in degenerating granule neurons. Taken
together, these results support the existing idea that zinc is released
into extracellular space and then enters neurons to exert a cytotoxic
effect. However, the origin of zinc is not likely to be synaptic
vesicles, because zinc accumulation robustly occurs in
ZnT3-null mice lacking synaptic vesicle zinc.
Key words:
TFL-Zn; neuronal degeneration; zinc transporter; kainate; cerebellum: CaEDTA
| |
INTRODUCTION |
In
the mammalian forebrain, an abundant pool of zinc is sequestered in
synaptic vesicles along with glutamate (Frederickson et al., 1987 ;
Frederickson, 1989; Danscher, 1996; Choi and Koh, 1998; Lee et al.,
1999). In contrast to metabolic zinc that is tightly bound to proteins,
this vesicular zinc is free or relatively weakly bound and hence
readily visualized with zinc-selective fluorescent dyes (Frederickson
et al., 1987; Budde et al., 1997; Suh et al., 1999; Lee et al., 2000)
or the neo-Timm's stain (Danscher, 1996). After neuronal excitation,
synaptic vesicle zinc is released into the synaptic cleft (Assaf and
Chung, 1984; Howell et al., 1984), where it may modulate the activity
of various ion channels (Peters et al., 1987; Westbrook and Mayer,
1987; Christine and Choi, 1990).
In addition to modulating neuronal transmission, zinc may contribute to
neuronal injury in certain pathological conditions. Suggesting this,
cytosolic zinc accumulation has been shown to correlate very well with
selective neuronal death in ischemia, seizures, and trauma
(Frederickson et al., 1988, 1989; Tonder et al., 1990; Koh et al.,
1996; Suh et al., 2000). Because of dynamic changes of zinc in the
synaptic vesicles, it has been proposed that extracellular release of
vesicular zinc and its subsequent uptake by postsynaptic neurons
underlie selective neuronal degeneration phenomena (the zinc
translocation hypothesis) (Frederickson, 1989; Choi and Koh, 1998; Lee
et al., 1999). However, this zinc translocation hypothesis, which
specifically implicates synaptic vesicle zinc as the source for the
toxic zinc accumulation, has not been directly proven.
Recently, it has been shown that zinc transporter 3 (ZnT3) is present
on the membranes of zinc-accumulating synaptic vesicles (Palmiter et
al., 1996; Wenzel et al., 1997). Furthermore, ZnT3 is considered
essential for the accumulation of vesicular zinc, because knocking out
the ZnT3 gene results in complete disappearance of zinc in
synaptic vesicles throughout the brain without affecting other
nonvesicular zinc pools in the mouse (Cole et al., 1999). Therefore,
ZnT3-null mice provide an ideal system for directly testing
the zinc translocation hypothesis. In the present study, this
hypothesis was tested in ZnT3-null mice by examining zinc accumulation in hippocampal neurons and their death after kainate seizures.
| |
MATERIALS AND METHODS |
Animals. ZnT3-null mice and their
wild-type (WT) littermates were bred and maintained in the facility of
University of Ulsan College of Medicine. Animals were allowed free
access to food and water at 24 ± 0.5°C and exposed to 12 hr
light/dark cycles. All animal experiments were performed according to
the Guidelines for Laboratory Animal Care and Use (University of
Ulsan). Before all experiments, genotyping for ZnT3 was
performed using the PCR method as described previously (Cole et al.,
1999).
Induction of seizures and scoring of seizure severity. Five
WT and ZnT3-null mice were injected intraperitoneally with
40 mg/kg kainate (Tocris Cookson, Bristol, UK) dissolved in 0.9% normal saline. Separately, 1 µl of 50 mM
kainate or a mixture of 100 mM
ZnCl2 and 50 mM kainate was
injected into the cerebellum of ZnT3-null mice. To determine
the effect of zinc chelation on kainate-induced seizure and neuronal
cell death, 2 µl of 300 mM CaEDTA in saline was
given stereotaxically into the lateral ventricle under anesthesia with
halothane in a 1:3 mixture of O2 and
N2O, beginning 30 min before kainate injection.
For 2 hr after kainate injection, seizure severity was behaviorally
estimated according to the classification of Peng et al. (1997). Two
hours after kainate injection, seizures were halted by intraperitoneal
injection of sodium phenytoin (50 mg/kg) (Lee et al., 2000). Features
of each seizure stage are as follows: stage 1, hypoactivity; stage 2, sedation; stage 3, hyperactivity; stage 4, scratching; stage 5, loss of
balance control; stage 6, tremors and generalized convulsions; and
stage 7, death.
Tissue preparation and zinc-specific fluorescence staining.
24 hr after kainate injection, brain was harvested, immediately frozen
in dry ice, and stored at  70°C. Coronal brain sections (10 µm
thick) including the hippocampus were prepared using the cryostat and
mounted on prechilled glass slides coated with
poly-L-lysine. Unfixed brain sections were stained with
N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulfonamide (TFL-Zn; Kd, 20 µM; Calbiochem, La Jolla, CA) dissolved in Tris buffer (0.1 mM, pH 8.0) for 90 sec (Budde et al.,
1997; Lee et al., 2000). After washing with saline, TFL-stained
sections were examined under a fluorescence microscope (excitation,
355-375 nm; dichroic, 380 nm; barrier, 420 nm; Olympus, Tokyo, Japan) and photographed.
Cell death detection by the terminal deoxynucleotidyl
transferase-mediated biotinylated dUTP nick end-labeling method.
To identify neuronal cell death in the sections, terminal
deoxynucleotidyl transferase-mediated biotinylated dUTP nick
end-labeling (TUNEL) staining was performed with the in
situ cell death detection kit, following the manufacture's
instruction manual (Boehringer Mannheim, Mannheim, Germany). After
fixation in 4% paraformaldehyde, the sections were incubated in 0.3%
H2O2 and in
permeabilization solution (0.1% Triton X-100 in 0.1% sodium citrate).
After TUNEL reaction, the sections were examined under a fluorescent
microscope and photographed.
Cell counting and acid-fuchsin staining. TFL-Zn fluorescent
(zinc-accumulating) neurons in the pyramidal layer of CA1 and CA3 were
counted in three coronal sections taken every 150 µm starting 4.2 mm
from bregma. Statistical comparisons were made using a two-tailed
t test. Adjacent brain sections were fixed overnight with
4% paraformaldehyde and stained with 1% acid-fuchsin (Lee et al.,
2000). After briefly rinsing in tap water, sections were immersed into
acid-fuchsin solution for 30 sec and washed with tap water. Acidophilic
(degenerating) neurons in CA1 and CA3 were counted under a bright-field microscope.
| |
RESULTS |
Consistent with previous studies (Frederickson et al., 1987; Koh
et al., 1996), TFL-Zn staining of the hippocampus of WT mice showed
that chelatable zinc was present densely in the mossy fiber terminals
and sparsely in other presynaptic fibers, including stratum radiatum of
CA1 (Fig. 1A). But
knocking out the ZnT3 gene resulted in complete
disappearance of zinc in synaptic vesicles throughout the brain (Fig.
1D), whereas it does not affect other nonvesicular
zinc pools in the mouse (Cole et al., 1999).
View larger version (67K):
[in this window]
[in a new window]
|
Figure 1.
A-F, Hippocampi from WT
(A-C) and ZnT3-null
(D-F) mice stained with TFL-Zn (A, B, D,
E) and the TUNEL method (C, F). A,
D, Controls; B, C, E, F, 24 hr after kainate
seizures. The TUNEL staining showed that CA1 neuronal death was greater
in ZnT3 null mice (C, F). Mice were
intraperitoneally injected with kainate (40 mg/kg). Two hours later,
seizures were halted by intraperitoneal injection of sodium phenytoin
(50 mg/kg). G, H, Treatment of hippocampal sections of a
kainate-injected ZnT3-null mouse with 10 mM
dithizone for 10 min completely removed TFL-Zn fluorescence from CA1
neurons (G), which was restored by the subsequent
incubation in 100 mM ZnCl2
(H) but not in FeCl2 or
CuCl2 solution (results not shown). Scale bars, 500 µm.
|
|
In the present study, WT and ZnT3-null mice
(n = 5 each) were intraperitoneally injected with 40 mg/kg kainate, a dose sufficient to produce severe seizures in all
mice. Because ZnT3-null mice are more sensitive than WT mice
to seizures induced by kainate (Cole et al., 2000), we chose this dose
to produce comparable seizures. To lessen the mortality (Lee et al.,
2000), seizures in both groups were stopped by intraperitoneally
injecting sodium phenytoin 2 hr after kainate injection. Using this
method, all mice developed seizures with similar time course and
severity, as estimated by the behavioral seizure severity scores of
Peng et al. (1997) (Fig.
2A).
View larger version (23K):
[in this window]
[in a new window]
|
Figure 2.
A, Time course for the progression
of seizure stages (mean ± SD; n = 5 each) in
WT or ZnT3-null mice without or with intraventricular
injection of 2 µl of 300 mM CaEDTA. See Materials and
Methods for the seizure classification. B,
Bars represent number of TFL-Zn(+) (right
bars) and acid-fuchsin(+) (left bars) neurons
(mean + SEM; n = 5) in bilateral CA1 in three brain
sections (10 µm thick) of WT, ZnT3-null mice, and
ZnT3-null mice injected with CaEDTA 24 hr after kainate
injection. Cell count was done on both sides of the hippocampus.
C, Number of TFL-Zn(+) and acid-fuchsin(+) neurons (mean + SEM; n = 5) in bilateral CA3 in the above
sections. *Difference from WT + KA; **Difference from ZnT3-null + KA
(p < 0.05, two-tailed t
test).
|
|
Staining brain sections of seizure-experienced mice 24 hr later with a
zinc-specific fluorescent dye, TFL-Zn, revealed dense zinc accumulation
in neuronal cell bodies and somewhat increased TFL-Zn fluorescence in
strata radiatum and oriens of not only WT (Fig. 1B)
but also ZnT3-null mice (five of five mice for each; Fig.
1E). The TFL-Zn fluorescence of ZnT3-null
mice was abolished by treatment with the zinc chelator-remover
dithizone (Fig. 1G). Staining with the TUNEL method or with
hematoxylin and eosin (Cole et al., 2000) revealed neuronal death in
densely TFL-Zn fluorescent cells in both WT and ZnT3-null
mice. Interestingly, whereas death of CA3 neurons in
ZnT3-null mice was less than that in WT mice, death of CA1
neurons in ZnT3-null mice was markedly enhanced compared with WT mice (Fig. 1C,F). Counting the number of
zinc-accumulating neurons and acid-fuchsin-stained neurons in CA1 and
CA3 confirmed this impression (Fig. 2B,C).
Next, we examined the possibility that cytosolic zinc in WT and
ZnT3-null mice originates from nonspecific release of zinc from degrading zinc-containing proteins. Arguing against this possibility, injection of kainate into the cerebellum resulted in
death, but not TFL-Zn staining, of granule neurons in both WT and
ZnT3-null mice (Fig. 3A). Only
when zinc was given with kainate did TFL-Zn fluorescence appear in most
TUNEL(+) cerebellar granule neurons (Fig. 3B). These results
are consistent with the previous report that zinc is not implicated in
kainate-induced granular cell death in the cerebellum (Frederickson et
al., 1989).
View larger version (122K):
[in this window]
[in a new window]
|
Figure 3.
A, Cerebellum of a
ZnT3-null mouse 24 hr after parenchymal injection of
kainate (1 µl of 50 mM), TFL-Zn stained and TUNEL
stained. Whereas the TUNEL method stained many granule neurons
(green fluorescence) around the injection site,
TFL-Zn stained none. B, Cerebellum of a
ZnT3-null mouse injected with 1 µl of kainate (50 mM) and zinc (100 mM). Most TUNEL(+) granule
neurons were stained also with TFL-Zn. Asterisks denote
injection sites. Scale bar, 500 µm.
|
|
To further examine whether toxic zinc accumulation originates from
outside the neurons, a cell membrane-impermeant zinc chelator was used.
Intraventricular injection of CaEDTA had little effect on
kainate-induced seizure severity in ZnT3-null mice (five of five mice; Fig. 2A) but markedly attenuated both zinc
accumulation and neuronal death in the hippocampus (Figs. 2,
4), favoring the external origin for
toxic zinc accumulation even in ZnT3-null mice.
View larger version (134K):
[in this window]
[in a new window]
|
Figure 4.
A, TFL-Zn fluorescence of
hippocampus of a CaEDTA-treated ZnT3-null mouse 24 hr
after kainate injection. Intraventricular injection of 2 µl of 300 mM CaEDTA markedly attenuated kainate seizure-induced zinc
accumulation in CA3 and CA1 neurons. B, TUNEL staining
of an adjacent brain section of A. CaEDTA injection
markedly reduced CA1 neuronal death (compare with Fig.
1F). Scale bar, 500 µm.
|
|
| |
DISCUSSION |
Although vesicular zinc is completely absent in
ZnT3-null mice, dense TFL-Zn fluorescence develops in
degenerating hippocampal neurons after kainate-induced seizures. This
result indicates that the main origin of zinc responsible for the
TFL-Zn fluorescence after brain injury in ZnT3-null mice is
not the histochemically reactive zinc stored in ZnT3-containing
synaptic vesicles. Although the present study cannot completely exclude
the possibility that certain adaptations in ZnT3-null mice,
such as alteration of metallothionein levels or other events related to
zinc homeostasis, may underlie the zinc accumulation in degenerating
neurons, overall our results suggest the nonvesicular origin of zinc
also in WT animals after brain injuries (Frederickson et al., 1988,
1989; Tonder et al., 1990; Koh et al., 1996; Suh et al., 2000).
Where does zinc accumulating in degenerating neurons of
ZnT3-null mice come from, if not synaptic vesicles? The
present study does not provide a specific answer to this question.
However, overall it suggests the external origin (i.e., from outside of zinc accumulating neurons) of zinc based on the following results. First, injection of kainate into the cerebellum resulted in death of
granule neurons but no TFL-Zn fluorescence in them in either WT or
ZnT3-null mice, arguing against the possibility that zinc is
nonspecifically released from degraded zinc-containing proteins. Only
when zinc was given with kainate did the fluorescence appear in the
TUNEL(+) granule cells. Corroborating this, Frederickson et al. (1989)
reported that zinc is not implicated in kainate-induced neuronal cell
death in the cerebellum. These results are consistent with previous
findings in cortical culture that excitotoxic, oxidative, or apoptotic
injury is not associated with zinc fluorescence unless zinc is added to
the exposure medium (Koh et al., 1996). Second, intraventricular
injection of a membrane-impermeant chelator, CaEDTA, blocks zinc
accumulation and neuronal death after seizures, ischemia, or trauma
(Koh et al., 1996; Cuajungco and Lees, 1998a; Lee et al., 2000; Suh et
al., 2000). Also in ZnT3 null mice, CaEDTA nearly completely
abolished zinc accumulation and neuronal cell death. These observations
favor an external origin of zinc, which implies transient increases in
extracellular zinc concentrations.
Although neuronal excitation could release a histochemically invisible,
ZnT3-independent pool of zinc, another possibility is that zinc may be
released intracellularly and then pumped out by transporters such as
zinc-efflux transporter 1 (ZnT1) (Palmiter and Findley, 1995; McMahon
and Cousins, 1998), raising local extracellular zinc concentrations.
ZnT1 is readily induced in the hippocampus in response to insults such
as ischemia (Tsuda et al., 1997). Once released to the extracellular
space, the zinc would be available for uptake into vulnerable
postsynaptic neurons via open ion channels (Frederickson et al., 1989;
Koh et al., 1996). However, although the complete blockade of zinc
accumulation and cell death by CaEDTA makes an external origin more
likely, the present study cannot completely rule out the alternative
possibility that zinc accumulation is an intrinsic event. For example,
it seems plausible that hippocampal neurons in vivo may have
a mechanism for internal release of zinc (Cuajungco and Lees, 1998b), a
feature not shared by cortical neurons in vitro or
cerebellar granule neurons in vivo, and that extracellular
CaEDTA somehow drives intracellular zinc out of these neurons.
Regardless of which of these possible mechanisms is operational, zinc
accumulation is likely a cause rather than a sequel of neuronal death,
because its blockade protects against neuronal death. However, contrary
to the current zinc translocation hypothesis (Frederickson, 1989; Choi
and Koh, 1998; Lee et al., 1999), the present results obtained from
ZnT3-null mice suggest that synaptic vesicle zinc may not be
the principal source of toxic zinc accumulation. Further studies seem
warranted to elucidate the detailed dynamics of zinc homeostasis in
brain injury.
| |
FOOTNOTES |
Received Feb. 8, 2000; revised March 20, 2000; accepted March 27, 2000.
This study was supported by Creative Research Initiatives of the Korean
Ministry of Science and Technology (J.-Y.K.).
Correspondence should be addressed to Jae-Young Koh, National Creative
Research Initiative Center for the Study of CNS Zinc, University of
Ulsan College of Medicine, 388-1 Poongnap-Dong, Songpa-Gu, Seoul
138-736, Korea. E-mail: jkko{at}www.amc.seoul.kr.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 2000, 20:RC79 (1-5). The
publication date is the date of posting online at
www.jneurosci.org.
| |
REFERENCES |
-
Assaf SY,
Chung SH
(1984)
Release of endogenous Zn2+ from brain tissue during activity.
Nature
308:734-736.
-
Budde T,
Minta A,
White JA,
Kay AR
(1997)
Imaging free zinc in synaptic terminals in live hippocampal slices.
Neuroscience
79:347-358.
-
Choi DW,
Koh JY
(1998)
Zinc and brain injury.
Annu Rev Neurosci
21:347-375.
-
Cole TB,
Wenzel HJ,
Kafer KE,
Schwartzkroin PA,
Palmiter RD
(1999)
Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene.
Proc Natl Acad Sci USA
96:1716-1721.
-
Cole TB,
Robbins CA,
Wenzel HJ,
Schwartzkroin PA,
Palmiter RD
(2000)
Seizures and neuronal damage in mice lacking vesicular zinc.
Epilepsy Res
39:153-169.
-
Christine CW,
Choi DW
(1990)
Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons.
J Neurosci
10:108-116.
-
Cuajungco MP,
Lees GJ
(1998a)
Diverse effects of metal chelating agents on the neuronal cytotoxicity of zinc in the hippocampus.
Brain Res
799:97-107.
-
Cuajungco MP,
Lees GJ
(1998b)
Nitric oxide generators produce accumulation of chelatable zinc in hippocampal neuronal perikarya.
Brain Res
799:118-129.
-
Danscher G
(1996)
The autometallographic zinc-sulphide method. A new approach involving in vivo creation of nanometer-sized zinc sulphide crystal lattices in zinc-enriched synaptic and secretory vesicles.
Histochem J
28:361-373.
-
Frederickson CJ
(1989)
Neurobiology of zinc and zinc-containing neurons.
Int Rev Neurobiol
31:145-238.
-
Frederickson CJ,
Kasarskis EJ,
Ringo D,
Frederickson RE
(1987)
A quinoline fluorescence method for visualizing and assaying the histochemically reactive zinc (bouton zinc) in the brain.
J Neurosci Methods
20:91-103.
-
Frederickson CJ,
Hernandez MD,
Goik SA,
Morton JD,
McGinty JF
(1988)
Loss of zinc staining from hippocampal mossy fibers during kainic acid induced seizures: a histofluorescence study.
Brain Res
446:383-386.
-
Frederickson CJ,
Hernandez MD,
McGinty JF
(1989)
Translocation of zinc may contribute to seizure-induced death of neurons.
Brain Res
480:317-321.
-
Howell GA,
Welch MG,
Frederickson CJ
(1984)
Stimulation-induced uptake and release of zinc in hippocampal slices.
Nature
308:736-738.
-
Koh JY,
Suh SW,
Gwag BJ,
He YY,
Hsu CY,
Choi DW
(1996)
The role of zinc in selective neuronal death after transient global cerebral ischemia.
Science
272:1013-1016.
-
Lee JM,
Zipfel GJ,
Choi DW
(1999)
The changing landscape of ischaemic brain injury mechanisms.
Nature
399:A7-A14.
-
Lee JY,
Park J,
Kim YH,
Kim DH,
Kim CG,
Koh JY
(2000)
Induction by synaptic zinc of heat shock protein-70 in hippocampus after kainate seizures.
Exp Neurol
161:433-441.
-
McMahon RJ,
Cousins RJ
(1998)
Mammalian zinc transporters.
J Nutr
128:667-670.
-
Palmiter RD,
Findley SD
(1995)
Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc.
EMBO J
14:639-649.
-
Palmiter RD,
Cole TB,
Quaife CJ,
Findley SD
(1996)
ZnT3, a putative transporter of zinc into synaptic vesicles.
Proc Natl Acad Sci USA
93:14934-14939.
-
Peng YG,
Clayton EC,
Means LW,
Ramsdell JS
(1997)
Repeated independent exposures to domoic acid do not enhance symptomatic toxicity in outbred or seizure-sensitive inbred mice.
Fundam Appl Toxicol
40:63-67.
-
Peters S,
Koh J,
Choi DW
(1987)
Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons.
Science
236:589-593.
-
Suh SW,
Listiack K,
Bell B,
Chen J,
Motamedi M,
Silva D,
Danscher G,
Whetsell W,
Thompson R,
Frederickson C
(1999)
Detection of pathological zinc accumulation in neurons: methods for autopsy, biopsy, and cultured tissue.
J Histochem Cytochem
47:969-972.
-
Suh SW,
Chen JW,
Motamedi M,
Bell B,
Listiak K,
Pons NF,
Danscher G,
Frederickson CJ
(2000)
Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury.
Brain Res
852:268-273.
-
Tonder N,
Johansen FF,
Frederickson CJ,
Zimmer J,
Diemer NH
(1990)
Possible role of zinc in the selective degeneration of dentate hilar neurons after cerebral ischemia in the adult rat.
Neurosci Lett
109:247-252.
-
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.
-
Wenzel HJ,
Cole TB,
Born DE,
Schwartzkroin PA,
Palmiter RD
(1997)
Ultrastructural localization of zinc transporter-3 (ZnT3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey.
Proc Natl Acad Sci USA
94:12676-12681.
-
Westbrook GL,
Mayer ML
(1987)
Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons.
Nature
328:640-643.
Copyright © 2000 Society for Neuroscience 0270-6474/00/$05.00/0
This article has been cited by other articles:
|
|
|
|
 
K. W. Leung, M. Liu, X. Xu, M. J. Seiler, C. J. Barnstable, and J. Tombran-Tink
Expression of ZnT and ZIP Zinc Transporters in the Human RPE and Their Regulation by Neurotrophic Factors
Invest. Ophthalmol. Vis. Sci.,
March 1, 2008;
49(3):
1221 - 1231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Lavoie, M. R. Peralta III, M. Chiasson, K. Lafortune, L. Pellegrini, L. Seress, and K. Toth
Extracellular chelation of zinc does not affect hippocampal excitability and seizure-induced cell death in rats
J. Physiol.,
January 1, 2007;
578(1):
275 - 289.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bonanni, M. Chachar, T. Jover-Mengual, H. Li, A. Jones, H. Yokota, D. Ofengeim, R. J. Flannery, T. Miyawaki, C.-H. Cho, et al.
Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain.
J. Neurosci.,
June 21, 2006;
26(25):
6851 - 6862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-M. Noh, H. Yokota, T. Mashiko, P. E. Castillo, R. S. Zukin, and M. V. L. Bennett
Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death
PNAS,
August 23, 2005;
102(34):
12230 - 12235.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Frederickson, W. Maret, and M. P. Cuajungco
Zinc and Excitotoxic Brain Injury: A New Model
Neuroscientist,
February 1, 2004;
10(1):
18 - 25.
[Abstract]
[PDF]
|
|
|
|
|
|
|
S. L. Sensi, D. Ton-That, P. G. Sullivan, E. A. Jonas, K. R. Gee, L. K. Kaczmarek, and J. H. Weiss
Modulation of mitochondrial function by endogenous Zn2+ pools
PNAS,
May 13, 2003;
100(10):
6157 - 6162.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Burdette and S. J. Lippard
Bioinorganic Chemistry Special Feature: Meeting of the minds: Metalloneurochemistry
PNAS,
April 1, 2003;
100(7):
3605 - 3610.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ueno, M. Tsukamoto, T. Hirano, K. Kikuchi, M. K. Yamada, N. Nishiyama, T. Nagano, N. Matsuki, and Y. Ikegaya
Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits
J. Cell Biol.,
July 22, 2002;
158(2):
215 - 220.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-Y. Lee, T. B. Cole, R. D. Palmiter, S. W. Suh, and J.-Y. Koh
From the Cover: Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice
PNAS,
May 28, 2002;
99(11):
7705 - 7710.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
Gene
