Metals in Brain - Biological Inorganic Chemistry - page 390

FIGURE 20.9 Coronal sections of rat midbrain. The tan-brown-black staining is the silver staining of zinc by the Timm-Danscher method.
With use of the electron microscope, all of the Timm-Danscher staining proves to be in the neuropil, in the presynaptic vesicles of gluzinergic
neurons. Timm stain in the hippocampus (H), piriform cortex (P), neocortex (N), and amygdala (A) was conspicuous in the wild type ZnT3 þ / þ
brain (a), reduced in the heterogeneous mutant ZnT3 þ / brain (b), and undetectable in the brains of homozygous mutant ZnT3 / mice (c).
(d) Higher magnification of the choroid plexus from the lateral ventricle (indicated area in (c). Timm stain was unperturbed in the ZnT3 / choroid
plexus.

(From Cole, Wentzel, Kafer, Schwartzkroin & Palmiter, 1999 . Copyright 1999 with permission from US National Academy of Sciences).

neuronal-specific zinc transporter ZnT3, as we saw above, a member of the large family of zinc transporters
(the ZnTs), which facilitate zinc efflux from the cytoplasm. ZnT3 and the vesicular glutamate transporter Vglut1
are found in the same vesicle population and the vesicular zinc concentration has been shown to be determined by
the abundance of ZnT3 protein. Thus, brains of mice carrying a targeted disruption of the ZnT3 gene (ZnT3 KO
mice) completely lack “chelatable zinc” ( Figure 20.9 ) .
Zinc is released into the synaptic cleft upon neuronal activity. Extracellular zinc has the potential to interact
with and modulate many different synaptic targets, including glutamate receptors and transporters. Zinc plays an
important role in synaptic plasticity in both the hippocampus and the amygdala, primarily by acting on post-
synaptic receptors. In early studies, it was shown that when hippocampal mossy fibres were stimulated, zinc was
released from synaptic vesicles into the synaptic cleft during neuronal activity. This release was both calcium and
depolarisation dependent. The release of zinc during synaptic transmission makes zinc available for entry into
cells through gated zinc channels on neighbouring cells. Since these zinc-releasing neurons also release glutamate,
the term “gluzinergic” has been proposed to describe them. The gluzinergic pathways are found almost exclu-
sively in the cerebral cortex and limbic system 5 (e.g., amygdala, cingulated cortex, hippocampus, and olfactory
bulb). While the fate of neuronally released zinc is not totally clear, it appears to modulate the overall excitability

5. The limbic system is a set of brain structures located on top of the brainstem and buried under the cortex. Limbic system structures are
involved in many of our emotions and motivations, particularly those that are related to survival. Such emotions include fear, anger, and
emotions related to sexual behaviour. The limbic system is also involved in feelings of pleasure that are related to our survival, such as those
experienced from eating and sex.