Metals in Brain - Biological Inorganic Chemistry - page 389

there are adequate zinc supplies for brain function and the prevention of neurological diseases. Zinc bound to
albumin within the plasma can be readily transferred to transporter proteins at the BBB. In mammalian brain, the
vast majority of zinc is tightly bounds within zinc metalloproteins in neurons and glial cells as a structural or as
a catalytic cofactor. However, approximately 10% of the total zinc, probably ionic zinc, is less tightly bound and is
mainly localised within the synaptic vesicles of the forebrain ( Figure 20.8 ), in a subset of glutamatergic axon
terminals. Such vesicular zinc is released into the synaptic cleft during neurotransmission and modulates NMDA-
specific postsynaptic receptors in a rapid dose-dependent response that is reversible. Zinc enhances GABA release
via potentiation of -amino-3-hydroxy-5-methyl-4-isoxalolepropionate (AMPA)/ kainate receptors in the CA3

region of the hippocampus, followed by a decrease in presynaptic glutamate release in the same region.
Zinc plays an important role in regulating brain development, particularly during foetal and early postnatal life.
During this developmental period, zinc deficiency adversely affects the autonomic nervous system regulation as
well as hippocampal and cerebellar development, leading to learning impairment and olfactory dysfunction.
Furthermore, the susceptibility to epileptic seizures (which may decrease vesicular zinc) is also enhanced by zinc
deficiency in vulnerable individuals. Zinc deficiency may lower the body's adaptability to stress. In this situation,
intracellular free calcium concentration may be altered prior to the decrease in zinc concentration in the extra-
cellular fluid. Anxiety-like behaviour, which is observed in animal models of induced zinc deficiency, can be
corrected to some extent, by the administration of zinc. This is due to the fact that zinc, which is an antagonist of
NMDA receptors, exhibits antidepressant-type activity, by inducing brain-derived neurotrophic factor (BDNF)
gene expression, which increases the synaptic zinc levels in the hippocampus. Preliminary clinical studies have
also demonstrated the benefit of zinc supplementation in antidepressant therapy.
On the other hand excessive synaptic release of zinc followed by entry into vulnerable neurons contributes to
severe neuronal cell death. This is caused by the sequential activation of Akt and GSK-3beta which play an
important role in directing hippocampal neural precursor cell death.
Zn 2 þ shows a variety of effects within the nervous system, thereby requiring that levels of zinc are regulated to
a very precise level. A fine balance between ion sequestration, intracellular buffering, and extrusion exists in order
to maintain cellular zinc homeostasis. A family of proteins known as metallothioneins regulates zinc sequestration
and buffering, while zinc uptake and extrusion is mediated by membrane-associated zinc transporters.
Mitochondria may serve as the pool of histochemically reactive zinc in neurons and glial cells.
Metallothioneins, MTs, are ubiquitous low-molecular-weight proteins high in cysteine and metal content and
devoid of aromatic amino acids, encoded by a multigene family. Human MTs bind up to seven zinc atoms and
contain 61

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68 amino acids, of which 20 are highly conserved cysteines. In the CNS, MTs show a diverse pattern
of expression with MT-1 and MT-2, mainly expressed in astrocytes and spinal glia, but largely absent from
neurons, whereas MT-3 is expressed exclusively in neurons and may play an important role in neuronal zinc
homeostasis as it is widely distributed in the brain associated with neurons containing synaptic zinc.
Mammalian zinc transporters belong to two gene families ( Cousins et al., 2006 ). Firstly, the ZnT (solute-linked
carrier 30

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SLC30) transporters decrease cytosolic zinc bioavailability by facilitating zinc efflux from cells and
promoting accumulation into intracellular vesicles. Secondly, the Zip family (solute-linked carrier 39

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SLC39)
increases cytosolic zinc by promoting the transport of extracellular and vesicular zinc into the cytoplasm. There
are ten human SLC30 genes. ZnT1 and ZnT3 have been co-localised with zinc in the synaptic vesicles. Vesicular
zinc concentration is determined by the abundance of ZnT3, and ZnT-3 is required for zinc transport into synaptic
vesicles. ZnT-1 is responsible for zinc efflux from the cell. Fourteen Zip genes have been characterised, many of
which are located at the plasma membrane, although Zip7 has been identified at the Golgi apparatus.
The mammalian forebrain contains a subset of glutamatergic neurons that sequester zinc in their synaptic
vesicles. Zinc-containing axon terminals are particularly abundant in the hippocampus, 4 the piriform cortex,
the neocortex, the striatum, and the amygdala ( Figure 20.9 ). Cytosolic zinc is transported into vesicles by the

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4. The hippocampus is a region of the brain important for learning and memory.