Zinc accumulation after target loss: an early event in retrograde degeneration of thalamic neurons.
Accumulation of cytoplasmic zinc is linked with a cascade of events leading to neuronal death. In many in vivo models of zinc-induced cell death, toxic concentrations of synaptically released zinc enter vulnerable neurons via neurotransmitter- or voltage-gated ion channels. In vitro studies demonstrate, in addition, that zinc can be liberated from intracellular stores following oxidative stress and contribute to cell death processes, including apoptosis. Here we describe accumulation of intracellular zinc in an in vivo model of cell death in the absence of presynaptic zinc release. We focused on the lateral geniculate nucleus (LGN) because LGN neurons undergo apoptosis when separated from their target, the primary visual cortex (V1), and the LGN is mostly devoid of zinc-containing presynaptic terminals. Infant and adult rats and adult mice received unilateral ablation of V1, either by aspiration or kainate injection. One to 14 days later, brain sections were stained with selenium autometallography or fluorescently labeled to localize zinc, or stained immunochemically for activated caspase-3. V1 lesions led to zinc accumulation in LGN neurons in infant and adult subjects. Zinc-containing neurons were evident 1-3 days after aspiration lesions, depending on age, but not until 14 days after kainate injection. Zinc accumulation was followed rapidly by immunostaining for activated caspase-3. Our data indicate that like neurotrauma and excitotoxicity, target deprivation leads to accumulation of zinc in apoptotic neurons. Moreover, zinc accumulation in vivo can occur in the absence of presynaptic zinc release. Together these findings suggest that accumulation of intracellular zinc is a ubiquitous component of the cell death cascade in neurons.
Land
Peter W
PW
Department of Neurobiology and Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. pland@pitt.edu
Aizenman
Elias
E
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans; D012183:Retrograde Degeneration / Q000378:metabolism* / Q000473:pathology; D013788:Thalamus / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D015032:Zinc / Q000032:analysis / Q000378:metabolism*
D015032:Zinc
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