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Journal of Neuroscience, Vol 16, 1337-1345, Copyright © 1996 by Society for Neuroscience
Loss of the p53 tumor suppressor gene protects neurons from kainate- induced cell death
RS Morrison, HJ Wenzel, Y Kinoshita, CA Robbins, LA Donehower and PA Schwartzkroin
Department of Neurological Surgery, University of Washington School of Medicine, Seattle 98195-6470, USA.
The tumor suppressor gene p53 recently has been associated with the
induction of cell death in response to some forms of cellular damage. A
possible role for p53-related modulation of neuronal viability has been
suggested by the finding that p53 expression is increased in damaged
neurons in models of ischemia and epilepsy. We evaluated the possibility
that p53 expression (in knockout mice) is required for induction of cell
damage in a model of seizure activity normally associated with well defined
patterns of cell loss. Subcutaneous injection of kainic acid, a potent
excitotoxin, induced comparable seizures in both wild-type mice (+/+) and
mice deficient in p53 (-/-). Using a silver impregnation technique to
examine neurodegeneration in animals killed 7 d after kainate injection, we
found that a majority of +/+ mice exhibited extensive cell loss in the
hippocampus, involving subregions CA1, CA3, the hilus, and the subiculum.
Apoptotic cell death, as identified with an in situ nick end labeling
technique to detect DNA fragmentation, was confirmed in CA1- but not CA3-
degenerating neurons. In marked contrast, a majority of p53 -/- mice
displayed no signs of cell damage; in the remaining p53 -/- mice, damage
was mild to moderate and was confined almost entirely to cells in CA3b of
the dorsal hippocampus. In +/+ mice, but not in -/- mice, damaged neurons
also were observed in the amygdala, piriform cortex, cerebral cortex,
caudate-putamen, and thalamus after kainate treatment. The pattern and
extent of damage in mice heterozygous for p53 (+/-) were identical to those
seen in +/+ mice, suggesting that a single copy of p53 is sufficient to
confer neuronal vulnerability. These results demonstrate that p53
influences viability in multiple neuronal subtypes and brain regions after
excitotoxic insult.
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