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*
NeuroBio Tex, Inc., Galveston, TX 77550,
MicroFab Technologies, Inc., Plano, TX 75075,
**
Biomedical Engineering, University of Texas Medical Branch, Galveston, TX 77550 and
University of Maryland, Baltimore, MD 21201
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT Brief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
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KEY WORDS: • zinc-containing neurons • glutamate • metallothionein • excitotoxicity GABA • Alzheimer’s disease
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Brief History and Overview of Zinc-Containing Neurons |
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TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
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) discovered the first zinc-containing presynaptic
vesicles. Although it is often overlooked, Haug actually went far
beyond merely describing the zinc-rich hippocampal mossy fibers: he
also described in elegant detail the complete zinc-containing
circuitry of the hippocampal formation, temporal lobe and, in fact, the
entire telencephalon (Haug 1975
). Moreover, the Aarhus
group led by G. Danscher and Haug also described the rapid release of
zinc from mossy-fiber boutons after surgical transection and the
physiological and histological effects of zinc chelators on
zinc-containing neurons (e.g., Danscher et al. 1973
,
1975
).
In the decades since the pioneering work of Haug and Danscher, our
knowledge of zinc-containing neurons has expanded dramatically. For
one thing, it is (mercifully) no longer necessary to refer to the
neurons with tongue-twisters like "neurons positive for
Timm’s-stainable metals." This is because there is no longer doubt
that the metal that can be stained in the axonal boutons of the
mammalian forebrain is zinc (Danscher 1984
,
1996
, Danscher et al. 1985
,
Frederickson et al. 1987
, 1992
).
Furthermore, the anatomical organization of the zinc-containing
circuitry that was sketched in the 1970s and 1980s by the Aarhus group
is gradually being reconfirmed and drawn in fine detail (and extended
to the human brain) with powerful new staining methods,
"autometallographic" and zinc-specific retrograde transport
methods (Casanovas-Aguilar et al. 1995
,
Christensen et al. 1992
, Danscher et al. 1997a,b
, Dyck et al. 1993
, Frederickson 1989
, Frederickson et al. 1992
, Long and Frederickson 1994
, Mandava et al. 1993
)
(Figs. 1
,2
,3
).
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, Erickson et al. 1997
, Palmiter et al. 1996a
,
1996b
) (Fig. 6)
. At the distal end of the neuron (the
bouton), the details of zinc storage in the vesicle, of exocytotic
release and of reuptake are gradually being revealed as well
(Colvin 1998a
, 1998b, Wenzel et al. 1997
). Finally, across on the postsynaptic side of the
synapse, zinc-specific recognition sites that modulate the
responsiveness of both excitatory and inhibitory amino acid receptors
have been identified and characterized (Frederickson, 1989
, Smart et al. 1994
) as having transmembrane
channels that admit zinc ions into the cytosol of certain postsynaptic
neurons under specific conditions (Yin et al. 1998
).
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It appears that all zinc-containing neurons are glutamatergic and
that only some glutamatergic neurons are zinc containing. This
relationship points toward a role of zinc in glutamate storage, release
or reuptake, or in modulation of glutamate receptors. Because the vast
preponderance of glutamatergic neurons that are zinc containing are in
the cerebral cortex and amygdala and the vast proportion of those that
are non—zinc containing are subcortical or spinal, many of us have
been tempted to speculate (with admittedly scanty evidence) that the
special importance of zinc in glutamatergic synaptic function might be
related to the cognitive and mnemonic operations unique to the cerebrum
(Frederickson et al.1990
).
As is often true in medical biology, it is easier to list pathological
symptoms of vesicular zinc dysregulation than to state the normal,
physiological functions of vesicular zinc. Thus, there is abundant
evidence that zinc might be a contributing cause of neuronal injury in
brain diseases or injuries that involve excitotoxic mechanisms of
neuron injury (Choi 1996
, Frederickson et al. 1988
). Specifically, the evidence suggests that during ischemia
(stroke), seizures or mechanical head injury, there is a released
"flood" of zinc from boutons that (1) depletes the
boutons of zinc and (2) allows toxic excesses of zinc to
enter postsynaptic neurons, causing injury or death. This "zinc
translocation" (Frederickson et al. 1988
) is arguably
among the leading preventable causes of neuronal injury in adult men
and women (Choi 1996
, Choi and Koh 1998
).
Still, the involvement of zinc in excitotoxicity does not explain why zinc is present in boutons in the first place or why it is released in a regulated fashion. The fact that synaptically released zinc enters postsynaptic neurons, however, raises the intriguing possibility that one of the physiological functions of zinc in the normal brain may actually involve the translocation from one (presynaptic) neuron into the next (postsynaptic) neuron, as a novel, orthograde, transcellular messenger.
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Zinc-Containing Neurons: Definition and Methods |
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TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
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,
Frederickson and Danscher 1990
). It now appears that the
zinc accumulates in these vesicles because of the presence of a
zinc-specific pump called zinc transporter-3
(ZnT-3)3
(Fig. 6
) that is itself localized on the membranes of the vesicles of these
same neurons (Palmiter et al. 1996b
, Wenzel et al. 1997
). Indeed, zinc-containing neurons may eventually
come to be defined by the presence of the ZnT-3 protein in their
vesicles (but see later).
It is worth noting in passing that the total amount of brain zinc that
is concentrated in the vesicles of the zinc-containing neurons is
quite small, probably < 5% of the total zinc in the brain
(Frederickson 1989
). This is rather like the situation
with glutamate: only a trivial quantity of glutamate is actually
sequestered in the vesicles of glutamatergic neurons, with the
remainder being present as a constituent of peptides and proteins.
Needless to say, the fact that the amount of stored material is small
does not make either vesicular glutamate or vesicular zinc unimportant.
However, it is tactically important for investigators to bear this in
mind. Instrumental bulk assays are almost certainly doomed to failure
when one is attempting to detect changes in the miniscule fraction of
zinc that is in the vesicles, compared with the larger fraction of
protein-bound material in whole brain.
Although the vesicular zinc is a small fraction of total zinc in the
brain, it constitutes virtually 100% of the histochemically reactive
zinc in the brain (Danscher 1985
, 1986,
1996
, Perez-Clausell and Danscher 1985
)
(Figs. 4
, 5
, 6
). This is a critically important datum: there
is no histochemically reactive zinc anywhere but in the secretory
vesicles of zinc-containing boutons (or en route in their axons).
Any staining for zinc in the nucleus, perikaryon or dendrites of
a neuron in the brain indicates either cell injury or artifact.
This fact is illustrated in the accompanying figures (Figs. 4
, 5
, 6)
that show that staining for zinc occurs only in the axonal boutons of
the zinc-containing neurons of the brain.
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, Danscher et al. 1997
, Frederickson et al. 1987a
, Suh et al. 1999
). For example,
almost any form of fixation masks subsequent staining of boutons,
causing less dense pathways to completely fail to stain and, with
prolonged hard fixation, causing all staining to fail. On the other
hand, treating tissue with harsh and aggressive reagents or simply
leaving the tissue to decompose in situ after death for a dozen hours
or so reliably causes (1) staining by some methods to be
completely blocked and (2) staining by other methods to be
dramatically amplified (Frederickson et al. 1987a
).
Finally, even with freshly cut, rapidly frozen, unfixed cryostat
sections of brain tissue, staining reagents that cannot penetrate the
lipid membranes of (largely intact) boutons and vesicles will still
fail to show the zinc in the axonal boutons (Suh et al. 2000).
Because the ZnT-3 protein is evidently present in all
zinc-containing vesicles, one could define and identify
zinc-containing neurons by the immunohistochemical loccalization of
the transporter, as well as by zinc histochemistry. The electron
microscopic survey of mossy-fiber neuropil in the rat indicates
that virtually all boutons have both ZnT-3 transporters as well as
zinc, indicating a possible equivalence of the two markers
(Wenzel et al. 1997
) (Fig. 6)
. However, whether there
are neurons that express the ZnT-3 gene but do not concentrate zinc in
their vesicles (due to post-translational modification of the
protein) is not determined. In fact, the mouse hippocampus shows rather
striking regional differences (especially in the lateral perforant
pathway and the direct, temporoammonic pathway) when stained for ZnT-3
in boutons compared with the staining for zinc in boutons
(Palmiter et al. 1996
, Wenzel et al. 1997
).
In addition to identifying the boutons, it is possible to selectively
label and identify the somata of zinc-containing neurons. Thus, if
one labels vesicular zinc by intravital precipitation of the zinc with
intravital selenium and then waits 24 h for retrograde transport
of the ZnSe, the neuronal somata that can then be visualized by ZnSe
histochemistry (the cells of origin of the ZnSe-labeled boutons)
are the zinc-containing somata (Danscher 1984
)
(Figs. 2,
7). When the selenium is administered intraperitoneally, the labeling is
weak and capricious, resulting in rather massive false-negative
errors (Slomianka et al. 1990
). On the other hand, when
the selenium is infused directly into the neuropil of interest, the
zinc-containing neurons with terminals in the infused region are
reliably and selectively labeled, with no known false-positives or
false-negatives (Frederickson, 1990
, Howell and Frederickson 1989
). Just as zinc-containing boutons can be
potentially identified by ZnT-3 immunochemistry, the
zinc-containing somata should be identifiable by visualization of
the ZnT-3 mRNA. This certainly is the case with some
zinc-containing neurons, such as the granule neurons of the dentate
gyrus, which are labeled by the ZnT-3 immunohistochemistry
(Palmiter et al. 1996
, Wenzel et al. 1997
). One assumes that it would be true for all of the
zinc-containing neurons, but as mentioned, some caution might be
advisable until the performance of a direct, double-staining
comparison of cell-by-cell labeling with the mRNA for ZnT-3 and
retrogradely transported ZnSe.
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Anatomy of the zinc-containing circuitry |
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TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
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, Christensen and Frederickson 1998
, Hill and Frederickson 1988
,
Perez-Clausell et al. 1989
, Slomianka et al. 1990
). Efferent zinc-containing fibers from these regions
are in turn directed almost exclusively to (1) cerebral
cortex and amygdala (2) striatum or (3)
"limbic" targets such as septum, nucleus of the diagonal band and
medial hypothalamus (Christensen and Frederickson 1998
,
Howell et al. 1991
, Long et al. 1995
,
Mandava et al. 1993
, Perez-Clausell et al. 1989
) (Figs. 1
, 2)
. This is in stark contrast to the other
chemospecific systems, such as cholinergic, serotonergic, adrenergic
and dopaminergic, all of which ascend from subcortical origins to
terminate diffusely throughout the hemispheres. One might say that the
zinc-containing neurons are an exclusive "output voice" of the
cerebral cortex and
amygdala.
It further appears that all zinc-containing neurons are
glutamatergic, with the zinc-containing neurons composing a select
subset of the broader set of all glutamatergic neurons. The evidence
for the zinc-glutamate link is of several types. On a macroscopic
level, it is clear that none of the major aminergic or cholinergic
systems have zinc-containing somata in the nuclear groups (i.e.,
basal nucleus of Mynert, Raphe nucleus or substantia nigra) from which
they originate (Frederickson 1989
). It is also clear
that zinc-containing boutons are conspicuously absent in regions
(e.g., the pyramidal stratum of the hippocampal formation) where the
terminals of GABAergic neurons are densely concentrated
(Perez-Clausell and Danscher 1985
).
On a finer level of analysis, colocalization studies have established
that boutons sequestering 
-aminobutyric acid (GABA) do not sequester
zinc (Beaulieu et al. 1992
), whereas boutons that are
immunoreactive for glutamate do include a high proportion of
zinc-containing boutons (Beaulieu et al. 1992
,
Wenzel et al. 1997
). This latter result is further
supported by the dendromorphology and location of the
zinc-containing neuronal somata that is seen after retrograde
labeling of the zinc-containing somata. Pyramidal neurons are the
rule in the neocortex and hippocampal formation; horizontally oriented
interneurons in nonpyramidal strata are essentially never labeled as
zinc-containing somata (Howell and Frederickson 1989
, Long et al. 1995
, 1997
,
Slomianka et al. 1990
). In view of the strength of the
evidence, it may be heuristically useful to identify these
zinc-containing glutamatergic neurons as "gluzinergic."
When viewed as a cerebral network, the zinc-containing system
appears to have several key anatomical "nodes." One such node is
the perirhinal cortex. Zinc-containing neurons in the perirhinal
cortex project widely throughout the neocortex and allocortex and to
the septum, as well (Howell et al. 1991
, Long et al. 1995
, Mandava et al. 1993
) (Fig. 2
). The perirhinal cortex arguably sends zinc-containing fibers
to more target regions that any other single efferent
zinc-containing system. The perirhinal cortex is also heavily
innervated by zinc-containing boutons, with the
entorhinal-perirhinal boundary always crisp and stark in zinc
histochemistry Fig. 4
.
A second "node" in the zinc-containing system is the small
blade of pyramidal neurons that lies in the confluence of the subiculum
and the hippocampal CA1 pryamidal field. The "prosubicular" neurons
(Long et al. 1995
, Mandava et al. 1993
)
are apparently all zinc containing. Like the perirhinal neurons, they
project to a large number of targets, including septum, subiculum and
several hippocampal fields. The neurons of the subiculum proper,
however, are entirely non–zinc containing (Long et al. 1995
, 1997
).
The amygdalar complex and the hippocampal formation (including the
subiculum) are also major points of convergence within the
zinc-containing neuronal network. All amygdalar nuclei receive some
zinc-containing input, and most of the nuclei also send
zinc-containing efferents to both local and remote targets
(Christensen and Frederickson 1998
, Christensen and Geneser 1995
, Howell et al. 1991
).
Amygdalofugal zinc-containing systems project broadly to the bed
nucleus of stria terminalis, pyriform cortex, striatum and
periamygdalar cortices. Like the amygdalar complex, the hippocampal
formation is another intriguing case. It appears to have four sets of
exclusively zinc-containing neurons (dentate granule neurons, CA3
pyramidal neurons, CA1 pyramidal neurons and prosubicular neurons)
arranged in a serial circuit that terminates in part within a fifth
population (subicular pyramids) that are entirely non—zinc containing
(Frederickson and Danscher, 1990
, Long et al. 1995
, 1997
). Another allocortical region with a
prominent population of exclusively zinc-containing neurons is the
pyriform cortex: all of the pyriform output pyramids are zinc
containing (Christensen et al. 1992
, Frederickson and Danscher 1990
).
One organizational feature of the zinc-containing neuroarchitecture
that stands out is that zinc-containing fiber systems tend to be
associational, rather that direct, long-pathway systems. In
particular, zinc-containing neurons are generally not found in
pathways that run either to or from thalamic, subthalamic, brain stem
or spinal structures. Instead, the zinc-containing systems are
generally corticocortical, corticolimbic or limbic-cortical.
Several examples of this pattern may be noted. In primary sensory
cortex, for example, zinc-containing boutons are conspicuously
absent in layer IV, where the primary thalamocortical afferents
terminate (Casanovas-Aguilar et al. 1995
, Dyck et al. 1993
). In fact, the boundaries between thalamocortical
input columns have some scattered zinc-containing inputs even in
layer IV, giving cortex such as the striate cortex and the barrel
fields a conspicuous, columnar appearance in tissue stained for
zinc-containing boutons (Dyck et al. 1993
). The
laminar segregation of zinc-containing and non–zinc-containing
fibers is especially interesting in view of the fact that both sets of
afferent fibers are glutamatergic.
The same pattern of exclusion of zinc-containing fibers is found in
the innervation of the striatum: corticostriatal fibers that have
collateral axons destined for the brain stem and cord (i.e., from Betz
cells) are not zinc containing, nor are those originating in brain stem
or subthalamus (Howell et al. 1989
). In contrast, the
corticostriatal fibers that arise from the small cortical pyramids of
layers II–IV and deep layer VI are zinc containing (Howell et al. 1989
).
On the corticofugal, efferent side, it is generally true that axons
destined for thalamic, brain stem or spinal targets are never zinc
containing, whereas those destined for cortical or "limbic" targets
(amygdalar, septal or hypothalamic) are in part zinc containing. This
is illustrated in the motor cortex, where none of the Betz cells are
zinc containing, and more broadly throughout the neocortex, where the
larger pyramidal neurons of layer V are virtually always non–zinc
containing (Casanovas-Aguilar et al. 1995
,
Slomianka et al. 1990
).
The same pattern of segregation can be seen in the hippocampal
formation, where the neurons giving rise to purely intrinsic fibers
(granule neurons, CA1 neurons) are all zinc containing (Haug 1967
, Wensel et al. 1997
) and the neurons
projecting to other cortical and limbic targets are zinc containing
(CA3 neurons; Long et al. 1997
), but the neurons that
have extensive basal forebrain and brain stem projections (subicular
neurons) are entirely of the non–zinc-containing variety (Long et al. 1995
, 1997
). The pyriform cortex
illustrates the same principle in yet another way: The principal
pyramidal neurons of the pyriform cortex project exclusively to
telencephalic targets (mostly cerebrocortical), and all of those
pyramidal neurons are zinc containing (Frederickson and Danscher, 1990
).
Why zinc is needed in cerebrocortical "associational" glutamatergic pathways but not in the "long axon" glutamatergic systems is enigmatic. Jacobson (1991) pointed out that neurons with large cell bodies and long axon (type I) are generally precocious and genetically "hard wired," whereas short axon small neurons (type II) are generally later-born and more plastic in both number and connections. One supposition is that vesicular zinc is somehow enabling to the plasticity of synaptic connections of the type II neurons.
To complete a discussion of the zinc-containing anatomy, it must be
noted that there are zinc-containing boutons in the dorsal cochlear
nucleus that appear to arise from intrinsic neurons, probably cochlear
granule neurons (Frederickson et al. 1989
). These
zinc-containing granule neurons are embryological sisters of the
cerebellar granule neurons. Both innervate their respective principal
cells with parallel fibers (Frederickson et al. 1989
)
and both are glutamatergic, yet one group is zinc containing (cochlear)
and the other is non zinc containing. Competitive-binding cDNA
expression comparisons of these two types of neurons would be
fascinating.
Beyond the cochlear nucleus, there are "Timm’s-positive" boutons
scattered through the thalamus, brain stem and spinal cord
(Haug, 1975
, Schroder et al. 1978
). There
also are submammalian species with Timm’s-positive boutons
(Holm et al. 1988
). Whether these boutons contain zinc
(which seems likely) or some other metal has not been established to
our knowledge. However, the best guess is that the metal is zinc, and
how these systems fit into the overall framework of gluzinergic
neuronal function can only be imagined.
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Molecular biology of zinc-containing neurons |
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TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
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Storage.
Zinc-containing neurons must accumulate, sequester and release zinc
from their presynaptic vesicles. The zinc transporter ZnT-3, which is
expressed exclusively in the brain (Palmiter et al. 1996
), apparently serves to pump zinc into the vesicles.
Knockout mice lacking the ZnT-3 gene have no histochemically reactive
zinc in their vesicles (T. B. Cole, personal communication) (Fig. 6)
. Moreover, mutant mice lacking a key protein involved in vesicle
cargo selection (mocha mice, lacking AP-3 d) are unable to
insert the ZnT-3 protein in the vesicles destined for the presynaptic
boutons, indicating that AP-3 is required to sort the ZnT-3 protein
into the neurosecretory vesicles. Like the ZnT-3 knockouts, the
AP-3–deficient mutants also fail to sequester zinc in the boutons of
their zinc-containing neurons (Kantheti et al. 1998
).
Another key protein group involved in zinc traffic is the
metallothioneins (MT) MT-I, MT-II and MT-III (Aschner et al. 1997
, Palmiter et al. 1996
). The MT are
metal-sequestering proteins. MT-3 is expressed only in the brain
and is preferentially located in regions (e.g., the hippocampal
formation) that have a high density of zinc-containing neurons
(Masters et al. 1994
). Mice lacking the MT-3 gene have
normal zinc in their zinc-containing boutons (Ericksen et al. 1997
), indicating that MT-3 is not an obligatory
carrier in the process of getting zinc into neurosecretory vesicles.
Moreover, because MT-3 is abundant in neurons that are not
zinc-containing neurons (e.g., the pyramidal neurons of the
subiculum and principal cells in the cerebellar deep nuclei), it
appears that MT-3 is not uniquely associated with zinc transport in the
zinc-containing neuron. The fact that MT-3 knockouts have no loss
of vesicular zinc (Ericksen et al. 1997
) bears this out.
Both ZnT-1 and ZnT-4 transport zinc out of cells, across the plasma
membrane (McMahon and Cousins 1998
). Although these
pumps would not be required within zinc-containing neurons per se,
they may be essential (along with MT-3) for neurons that receive
zinc-containing synaptic input (i.e., zinoceptive neurons), as
discussed later.
Zinc-containing neurons must concentrate zinc intracellularly and then
concentrate the zinc further within the secretory vesicles that are
destined for the boutons. There is essentially unanimous agreement
(Beaulieu et al. 1992
, Haug 1967
,
Palmiter et al. 1996
, Perez-Clausell and Danscher 1985
) that the zinc is exclusively located in the small clear
round vesicles (of glutamatergic neurons). How much zinc is actually in
those vesicles is undetermined, but it can be roughly estimated from
prior data that show the amount of zinc in the neuropil of one
zinc-containing pathway (hippocampal mossy-fiber pathway)
350 µmol/L in the wet tissue (Frederickson et al. 1982
, calculations in Frederickson 1989
,
Wensink et al. 1987
). To our knowledge, the volume
fraction of vesicles in the mossy-fiber neuropil has never been
calculated, but there is no doubt that it is among the highest in the
brain. (This is, after all, why the mossy-fiber stratum was
originally called "stratum lucidum.") An order-of-magnitude guess
would be that the vesicles account for 25% of the tissue volume. This
implies that vesicles contain concentrations of zinc up to four times
350 µmol/L: 1.4 mmol/L.
The transporter ZnT-3 that decorates the membranes of small clear round
vesicles (Wenzel et al. 1997
) is presumably responsible
for maintaining the high intravesicular zinc content. It is not
possible to stain zinc in vesicles in the soma or Golgi apparatus of
zinc-containing neurons, even after treatment with colchicine
(unpublished observation). It is, however, possible to stain the
vesicles in transit in the axons (e.g., Frederickson and Danscher 1990
)
and, of course, at their destination in the presynaptic boutons. This
suggests that the zinc is steadily accumulated in the newly formed
vesicles after they leave the Golgi apparatus and while they are in
transit to the boutons. One possible explanation for the high
variability of zinc staining among individual vesicles
(Perez-Clausell and Danscher, 1985
) is that denser
staining simply indicates more "mature" vesicles that have taken up
more zinc.
The availability of zinc in the cytosol for transport into vesicles by
ZnT-3 is governed by (1) passive channel-mediated flux
into or out of the cell, (2) active uptake into the cell,
(3) export out of the cell and (4) intracellular
zinc–binding ligands. Passive flux through the neuronal membrane
occurs when the extracellular level of free zinc is high, as happens
when either exogenous zinc is added to a culture medium or when the
zinc-containing boutons in the tissue "dump" their vesicular
zinc in massive excess, as occurs during excitotoxic events.
Weiss et al. (1995) characterized three
zinc-permeable channels that can be demonstrated in dissociated
neuron cultures: (1) a zinc- and calcium-permeable
voltage-controlled channel, (2) an
N-methyl-D-aspartate (NMDA)-gated
channel and (3) an 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
(AMPA)/KA-gated channel. All three of those channels allow zinc influx
when exogenous zinc is added to the medium in amounts (i.e., < 30
µmol/L) that are not cytotoxic.
The active pumping of zinc into neurons or isolated synaptosomes has
been explored by several groups who have identified
energy-dependent transport with apparent
Km values that range from 0.2 to 10
µmol/L (Colvin 1998
, Colvin et al. 2000
, Howell et al. 1984
, Wensink et al. 1988
). Similar results have been obtained with other cell types
(Chang et al. 1998
, Gisbert-Gonzalez & Torres-Molina 1996
, Eide 1997
). However, as
Wensink et al. (1988
) pointed out, there is almost
certainly substantial error involved in experiments that simply add
micromolar amounts of Zn2+ salt to a tissue
system. One source of error is the well-established fact that even
a Zn2+ concentration of 100 µmol/L or
so kills cells rather quickly (Yokohama et al. 1986
). The other source is that zinc-binding ligands in the
extracellular medium of a cell preparation (albumin, histidine,
glutathione, and so on) will avidly bind Zn2+,
reducing the true concentration of free zinc ion to far below the
amount of added zinc ion (total zinc) (Wensink et al. 1988
). The use of a "zinc buffer" at a maximum of 10
µmol/L or so solves these problems.
Once free zinc enters a cell, sequestering by MT, calmodulin, S100,
tubulin and other ligands is inevitable; the resting level of
intracellular zinc in neurons is probably in the range of 50–500
pmol/L (Cheng and Reynolds 1998
). This implies that the
ZnT-3 pump can concentrate zinc in vesicles against a gradient of eight
orders of magnitude.
It is worth noting that the concentration of zinc in presynaptic
vesicles of neurons is part of a broad and constant pattern in zinc
metabolism wherein certain types of secretory cells concentrate large
amounts of weakly coordinated zinc within their secretory granules. We
have referred to this as "storage granule zinc" in the past.
Examples abound. Storage granule zinc is found the insulin granules of
ß-cells (Dodson and Steiner 1998
), in salivary gland
cells (Frederickson et al. 1987
), in a variety of
leukocyte secretory granules (Danscher, G. & Frederickson, C. J., unpublished results) and in pituitary secretory cells
(Thorlacius-Ussing et al. 1985
). Zinc (and other
exogenous metals) will also be routinely found in perikaryal endosomes
whenever cells or tissue are challenged with an excess of metals. This
is found when many cell types are exposed to toxic metals
(Rungby et al. 1990
) and when tissues, such as gill
tissue, are exposed to excess metal ions in the water (e.g.,
Baatrup and Danscher 1987
).
Recent evidence suggests that the tendency of cells to sequester metal
in vesicles is also triggered when they are maintained in dissociated
cell culture. Both Zalewski (2000) and O’Halloran (2000) have
adduced evidence that endosomal sequestration may occur under these
conditions. Because healthy control neurons never show any perikaryal
endosomal zinc deposits in vivo (Howell and Frederickson, 1989
, Perez-Clausell and Danscher 1985
,
1986
), the factors that induce this event in cultured
cells or cells challenged with excess metal will be intriguing to
understand.
Release.
The release of zinc from the presynaptic vesicles of
zinc-containing neurons is depolarization and calcium dependent
(Howell et al. 1984
) and probably occurs via the
mechanism of exocytosis of the small clear round vesicles in which
silver staining shows the zinc (Perez-Clausell and Danscher, 1986
). Many groups have demonstrated release (Aniksztejn et al. 1987
, Assaf and Chung 1984
,
Sloviter 1985
). Release has an apparently high
Q10, being virtually completely blocked at room
temperature (20–26°C) and vigorous in the range of normal rat body
temperature, 37–39°C (Frederickson et al. 1998
). This
explains why experiments done at or near room temperature basically
fail to demonstrate physiological release of zinc (Kay et al. 1995
). Furthermore, in the case of conventionally cut brain
slices, it turns out that up to half of the bouton zinc is
irretrievably lost through the act of cutting the slice
(Frederickson et al. 1998
). These two problems are major
obstacles to the study of zinc release in the typical in vitro slice
preparation. They may also explain why zinc chelation typically
produces only weak or mixed effects on monosynaptic evoked responses in
the in vitro slice preparation when tested below normal rat body
temperature (Easley et al. 1993
, Frederickson 1989
, Xie and Smart 1994
).
Essentially nothing is known about the kinetics of zinc release. We
previously speculated that zinc release might be sharply nonlinear with
frequency of firing, based on fairly scanty evidence (Easley et al. 1993
), but there are no real data on this point. One
assumes that zinc and glutamate are coreleased, and there certainly are
many conditions in which both substances can be shown to have been
released, such as after ischemia, seizures and blunt trauma
(Frederickson et al. 1988
, 1998
,
Sorensen et al. 1998
). Still, the corelease of glutamate
and zinc has never been directly demonstrated or characterized, an
important oversight in this field.
It has been shown clearly in many laboratories that the total amount of
zinc stored in vesicles can be released quickly, with a resulting
depletion of the boutons. This was first reported by Sloviter in 1985,
and is seen best after excitotoxic insult (seizures, head injury,
ischemia) when the loss of stainable zinc from the boutons can be
virtually complete within as little as 1 h (Frederickson et al. 1988
, Koh et al. 1996
, Sorensen et al. 1998
, Suh et al. 1995
, 1996
,
Tonder et al. 1990
). Where the zinc goes after release
is not yet fully resolved (see later). However, in situ labeling of the
zinc in an effort to "follow" released zinc has revealed some
intriguing complexity of the release process. Thus, precipitating the
zinc in situ in the vesicles with sulfide in vivo leads to an almost
complete translocation of the ZnS into the cleft or to the presynaptic
specialization within 12 h (Perez-Clausell and Danscher 1986
), whereas precipitating in situ with selenium leads to
some exocytosis but a preferential retrograde transport of the
ZnSe-filled vesicles to the perikaryon (Howell and Frederickson 1990
) (Fig. 7)
. Binding zinc in vitro with
lipophilic, toluene sulfonamid quinoline (TSQ) derived
chelators leads to a relative immobilization of the zinc-quinoline
complex in the membranes (Andrews et al. 1995
,
Kay et al. 1995
). In short, once the speciation of the
relatively weakly-bound zinc has been perturbed in the vesicles,
whatever happens thereafter is variable and nonphysiological.
|
,
9). The kinetics and biophysics of this release are under investigation
with this method.
|
, Howell and Frederickson 1984
,
O’Halloran 2000, Wensink et al. 1988
).
However, it is important to recall that zinc-containing boutons can
readily be depleted of their stainable zinc by intense activation in
vivo and in vitro (Frederickson et al. 1998
). This is
quite different from small molecule transmitters, such as the amines or
acetylcholine, which are generally not depleted during intense
activation unless reuptake is blocked. Thus, in the zinc-containing
bouton, either reuptake of zinc into boutons is quantitatively
unimportant or, plausibly, the pathological conditions that lead to
zinc "dumping" also lead to inhibition of the putative zinc
reuptake system. The latter scenario appears to occur with glutamate,
with which both accelerated released and suppressed reuptake occur in
some excitotoxic situations (Zhao et al. 1997
). The
modulation of zinc reuptake is a potentially important therapeutic
strategy for neuroprotection against excitotoxicity.
Besides reuptake and penetration into postsynaptic neurons, the third
major "sink" for released zinc is the population of
zinc-binding ligands in the extracellular fluid, including albumin,
glutathione, histidine and others. These are present at low micromolar
concentrations and have Kd values for
zinc binding in the low nanomolar range (Wensink et al. 1988
). Thus, so long as they are not saturated by an excess of
zinc, these "scavengers" would be expected to rapidly remove the
ionic zinc released from zinc-containing boutons, maintaining the
low nanomolar extracellular concentration during normal physiological
conditions.
|
Normal physiological function of synaptic zinc |
|---|
|
TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
|---|
One venerable notion of the role of zinc is that the zinc in the
vesicle is important for glutamate storage. In theory, zinc could
either increase the storage capacity (by polymerization/precipitation
of the glutamate) or slow the release rate of glutamate by imposing the
slow kinetics of some Glu-Zn dissociation process. These theories
are weakened (although not fatally) by the fact that many groups have
found that removal of the endogenous zinc through chelation or
precipitation has no demonstrable effect on the single-pulse,
monosynaptic evoked response at zinc-containing synapses
(Easley et al. 1995
, Mitchell and Barnes 1993
, Xie et al. 1994
).
Concerning the role or roles of zinc in the cleft, it is quite clear
that zinc ions are powerful modulators of both ionotropic and
metabotropic NMDA and KA receptors for glutamate. Zinc-specific
binding sites have been identified (Smart et al. 1994
),
and the effects of zinc are seen at concentrations in the range of
1–10 µmol/L, a level that would be easily obtained in the immediate
microenvironment of a zinc-containing bouton during zinc release
(see later).
The functional significance of the modulatory role of zinc is hard to
predict, because both up- and down-regulation of receptor function
occur at different receptors (Smart et al. 1994
), and
even at different splice variants of the same receptor (Hollmann et al. 1994
). This notwithstanding, most evidence suggests that
zinc is predominantly defacilitatory, or anticonvulsant, when whole
animal or brain slice systems are tested. Thus, zinc chelation is
frankly proconvulsive (Mitchell et al. 1990
,
Mitchell and Barnes 1993
), and knockout mice
(ZnT-3-/-) lacking vesicular zinc are
especially seizure prone (Wenzel et al. 1997
). The
intracerebral administration of Zn2+ kills
neurons (Lees et al. 1998
, Yokahama et al. 1986
), so any anticonvulsive (or proconvulsive effect) is
essentially impossible to assess in the face of the direct damage.
As mentioned earlier, the removal of zinc through chelation or
precipitation has little or effect on the monosynaptic evoked response
at glutamatergic, zinc-containing synapses. There is some evidence
that the synaptic function observed during high frequency driving might
be selectively sensitive to zinc depletion (Easley et al. 1995
), but this is controversial (Xie et al. 1994
). In any event, the discovery of a preparation and
paradigm that would reveal a robust and consistent effect of removing
the normally present, endogenous zinc from the presynaptic vesicles
would be a major advance for the field.
Beyond the glutamatergic synapse, there are dozens of
membrane-spanning proteins sensitive to zinc, including receptors,
channels, pumps and proteins such as ß-amyloid and
-macroglobulin (Frederickson 1989
,
Smart et al. 1994
). Among these, the GABA receptor has
received especially active attention and has proved to be sensitive to
micromolar amounts of zinc. Although the complete story is complex
(Smart et al. 1994
), there appears to be some consensus
that zinc ions decrease inhibitory drive from the
GABAA receptor in the normal adult, a notion that
is hard to fit with the generally proconvulsive effects of zinc
depletion noted earlier.
Ultimately, which of the zinc-sensitive proteins in the brain
will actually be modulated by zinc will depend on whether zinc ions
could ever reach the proteins in question. In this regard, it is useful
to consider concentrations. If a single bouton [e.g., 1
µm3 (10-15 L) in
volume] had 1 mmol/L average zinc content, it would release 1
10-18 moles, or 105 zinc
ions. This assumes a massive, complete "dump" of all the zinc of
the bouton. Within only a 15-µm radius from the bouton, the ions will
be diluted by 1:153 (1:3000), i.e., from 1
mmol/L to 300 nmol/L. Because only 10% of that volume is
extracellular fluid, the extracellular concentration could reach 3
µmol/L, which is near threshold for most zinc-sensitive receptors
(Smart et al. 1994
). However, the binding of the
Zn2+ to extracellular ligands such as albumin and
glutathione alone (both present at 1 µmol/L in the cerebrospinal
fluid and both with Kd values in the
nanomolar range; Cousins 1986
, Wensink et al. 1988
) would rapidly lower that 3 µmol/L
Zn2+ to the low nanomolar range.
In short, the "zinc signals" released from gluzinergic terminals
may normally travel no more than a few microns before dissipating into
the background zinc. Thus, for example,
GABAA receptors studding the membranes of granule
neuron somata may never be reached by zinc ions that can only be
released from boutons up in the molecular dendritic zone or the
subgranular hilar zone of those granule neurons. On the other hand,
where GABA receptors are strewn amid gluzinergic boutons, as in the
stratum radiatum dendritic zone of the hippocampus (Sperk et al. 1997
), synaptically released zinc could potentially modulate
GABA function.
The third, and most speculative, of the possible roles of zinc are
those that could come into play if zinc ions were to move from the
presynaptic bouton into the interior of postsynaptic neurons. This
admittedly heretical idea has no direct support, but it is indirectly
supported by the evidence that zinc is apparently translocated in just
such fashion during excitotoxic brain injury (see later). There are
literally dozens of intracellullar proteins that are sensitive to zinc
ions (Cuajungco and Lees 1997
), including those in the
cytosol, in mitochondria and, perhaps most intriguingly, in the
nucleus. There is evidence that zinc ions in physiologically extreme
conditions can modulate the probability of apoptosis (Aiuchi et al. 1998
, Cuajungco and Lees 1997
). Virtually
all DNA-binding proteins are zinc finger proteins (Choo and Klug 1997
). The possibility that zinc signals might play on
that family of gene-regulatory proteins, guiding gene expression in
vital ways, makes zinc potentially the most powerful of all synaptic
messenger substances. Direct testing of whether synaptically released
zinc enters postsynaptic neurons is critically needed.
Synaptically released zinc and pathology.
Excitotoxicity. Synaptically released zinc is directly implicated in the phenomenon of excitotoxicity, in which brain tissue deprived of oxygen, glucose or both begins to release massive amounts of excitatory amino acid transmitter (e.g., glutamate), neurons are tonically depolarized and cell death, both immediate and delayed, ensues.
The first evidence of the role of zinc in excitotoxic neuron
death was obtained in rats that had experienced kainic acid
(KA)-induced seizures (Frederickson et al. 1988
)
(Fig. 12
), a finding that capitalized on earlier evidence of the toxicity of
zinc to cultured neurons (Yokohoma et al. 1986
). That
seizure result was soon replicated (Frederickson et al. 1989
) and extended to the ischemia model (Tonder et al. 1990
), with the basic finding that zinc (1)
disappeared from presynaptic boutons and (2) appeared
selectively in dying postsynaptic neurons during excitotoxic events.
The notion that such "translocation" (Frederickson et al. 1989
) of zinc from presynaptic boutons to postsynaptic neurons
could kill the target neurons was finally given a definitive and direct
test in 1996 by Koh et al. (1996
), who marshalled quite
elegant and convincing data on that point.
|
,
Suh et al. 1995
), seizures (Frederickson et al. 1988
, Sloviter 1985
, Suh et al. 1996
) and traumatic head injury (Long et al. 1998
) (Fig. 11
). Moreover, several groups have repeated and extended the basic
zinc-chelation/neuroprotection phenomenon, which is as follows. In
paradigms in which neuron death is produced by ischemia, seizures, or
traumatic head injury, the simple expedient of chelating extracellular
zinc just before (and during) the insult will protect neurons from the
excitotoxic injury, yielding up to 85% neuron sparing compared with
the unprotected control situation (Choi and Koh 1998
,
Koh et al. 1996
, Long et al. 1998
,
Suh et al. 1995
, 1996
).
|
, Mitchell and Barnes 1993
). The failure of
membrane-permeable compounds to afford neuroprotection is
presumably due to the fact that the inactivation of essential
zinc-dependent biochemistry inside neurons is directly cytotoxic,
even cytolethal (McCabe et al. 1993
, Zalewski et al. 1994
). Likewise, an extracellular chelator that cannot
reduce extracellular Zn2+ (Zn-EDTA) has no
protective effect, as one would expect (Koh et al. 1996
,
Long et al. 1998
, Suh et al. 1995
,
1996
).
Weiss and coworkers have shown that zinc ingress into neurons during
excitotoxic conditions occurs via three channels: an NMDA-gated
channel, a voltage-dependent channel and an AMPA/KA-gated channel
(Weiss et al. 1993
, Yin and Weiss 1995
,
Yin et al. 1998
). The last of these is apparently
expressed only in select neurons (which are thus selectively
vulnerable) and can carry a much higher zinc "current" that the
others. Thus, cells with the KA/AMPA channel are most at risk for
zinc-mediated neuron death (Yin et al. 1998
).
The details of zinc-induced neuron death are only now emerging, but
one mechanism appears to be mitochondrial poisoning, because the
ingress of zinc produces a correlated rise in reactive oxygen species
(Carriedo et al. 1998
). Another line of evidence has
indicated that zinc influx can trigger apoptosis in target neurons
(Manev et al. 1997
, Telford and Fraker 1997
). On the other hand, it is also true that zinc deficiency
can trigger apoptosis in some cells and model systems (Ahn et al. 1998
), with zinc administration providing a remedial
decrease in the apoptosis (McCabe et al. 1993
,
Zalewski et al. 1994
). Thus, the exact mechanism of
zinc-induced neuron death remains unresolved.
In addition to the harm done by zinc entering the neurons, it should be
mentioned that the high Zn2+ concentrations
occurring extracellularly could also exacerbate the excitotoxic
cascade. To be specific, elevated extracellular
Zn2+ can (1) impede the reuptake of
glutamate (Vendenburg et al. 1998
),
(2) increase membrane depolarization through the
up-regulation of KA/AMPA receptors (Peters et al. 1987) and some splice variants of NMDA receptors
(Hollmann et al. 1994
) and (3) contribute to
Ca2+ dysregulation via effects on
Ca2+ pumps (Colvin 1998
).
Alzheimer’s disease.
An excellent article on zinc and Alzheimer’s disease is given by
Huang et al. (2000
) and shows the intricate
role of zinc (potentially synaptically released zinc) in the etiology
and symptomology of that disease. The general notion emerging is that
synaptically released zinc can interact with Aß 1-42
protein, causing the latter to precipitate into plaques and
perivascular angiopathy. The major points of evidence are that
(1) plaques form preferentially in brain regions densely
innervated by gluzinergic fibers; (2) micromolar amounts of
Zn2+ precipitate Ab, potentially causing
the formation of Ab-rich dense-core plaques in the brains of
patients with Alzheimer’s disease; (3) zinc chelation can
solubilize plaque material from brain homogenate; (4)
plaques in brain tissue obtained at autopsy from patients with
Alzheimer’s disease are enriched with as much as 1 mmol/L zinc
(Lovell et al. 1998
); and (5) both the tissue
distribution of zinc and the histochemical staining for zinc have been
reported to be disturbed in Alzheimer’s disease (Constantinidis 1990
, Danscher et al. 1997
) (Fig. 13
). This last histochemical observation has recently been confirmed and
extended in our laboratory in data showing that the dense-core
plaques and the perivascular, angiopathic amyloid deposits are rich in
histochemically reactive zinc (Suh et al. 1998
) (Fig. 13)
. Whether zinc-induced precipitation of the Aß into plaques is
ultimately neuroprotective or neurodestructive is not fully resolved.
|
), and there is
one report suggesting that acute immobilization stress can cause some
release of zinc from the hippocampus (Itoh et al. 1993
)
(Fig. 12)
. We have begun to explore a possible role of stress and the
stress hormones in the mobilization and release of zinc from the
boutons of gluzinergic neurons, with some intriguing preliminary
findings. The first is that the adrenal glucorticoid appears to
modulate the level of zinc that is sequestered in the boutons of the
gluzinergic neurons. Thus, surgical adrenalectomy causes a drop in the
level of bouton zinc in some hippocampal neuropil within as little as
10 d after surgery. This is well before the loss of granule
neurons is pronounced and occurs in the absence of a measurable loss of
mossy-fiber bouton zinc (Suh et al. 1997
). One
plausible mechanism linking the glucocorticoid driving of zinc levels
would be that glucocorticoid signals increase the rate of synthesis of
peptides or proteins (such as nerve growth factor) that might be
colocalized with zinc in the presynaptic vesicles.
More recently, we have begun exploring the effects of stress on the
release of zinc from gluzinergic boutons. The preliminary finding is
that rats subjected to immobilization stress for 4 h show a
dramatic loss of bouton zinc compared with rats that are simply left in
the home cage (Fig. 12
). One especially interesting note about this preliminary result is that
we have not seen it in rats that were not pretreated with an
extracellular zinc chelator (Ca-EDTA). This implies that the stress
actually increases bouton turnover of zinc, a result that will be
missed unless the reuptake process is impeded by extracellular
chelation of the zinc before reuptake. The implications of a possible
stress modulation of zinc storage and zinc release are far reaching.
|
Conclusions |
|---|
|
TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
|---|
|
|
|
FOOTNOTES |
|---|
3 Abbreviations used: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, -aminobutyric acid; KA, kainic acid; NMDA, N-methyl-D-aspartate; MT, metallothionein; ZnT, zinc transporter.
|
REFERENCES |
|---|
|
TOPABSTRACTBrief History and Overview...Zinc-Containing Neurons:...Anatomy of the zinc-containing...Molecular biology of zinc...Normal physiological function of...ConclusionsREFERENCES |
|---|
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