Jy. Lee et al., Accumulation of zinc in degenerating hippocampal neurons of ZnT3-null miceafter seizures: Evidence against synaptic vesicle origin, J NEUROSC, 20(11), 2000, pp. RC79-NIL_8
In several brain injury models, zinc accumulates in degenerating neuronal s
omata. Suggesting that such zinc accumulation may play a causal role in neu
rodegeneration, zinc chelation attenuates neuronal death. Because histochem
ically reactive zinc is present in and released from synaptic vesicles of g
lutamatergic neurons in the forebrain, it was proposed that zinc translocat
ion from presynaptic terminals to postsynaptic neurons may be the mechanism
of toxic zinc accumulation. To test this hypothesis, kainate seizure-induc
ed neuronal death was examined in zinc transporter 3 gene (ZnT3)-null mice,
a strain that completely lacks histochemically reactive zinc in synaptic v
esicles. Intraperitoneal injection of kainate induced seizures to a similar
degree in wild type and ZnT3-null mice. Staining of hippocampal sections w
ith a zinc-specific fluorescent dye, N-(6-methoxy-8-quinolyl)-p-carboxybenz
oylsulfonamide, 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 alm
ost 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 o
f kainate into the cerebellum did not induce zinc accumulation in degenerat
ing granule neurons. Taken together, these results support the existing ide
a 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 m
ice lacking synaptic vesicle zinc.