Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death

Richard S. Morrison, H. Jurgen Wenzel, Yoshito Kinoshita, Carol A. Robbins, Larry A. Donehower, Philip A Schwartzkroin

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1337-1345
Number of pages9
JournalJournal of Neuroscience
Volume16
Issue number4
StatePublished - Feb 15 1996
Externally publishedYes

Fingerprint

Kainic Acid
Tumor Suppressor Genes
Cell Death
Neurons
Hippocampus
Seizures
Putamen
In Situ Nick-End Labeling
Neurotoxins
DNA Fragmentation
Subcutaneous Injections
Amygdala
Thalamus
Silver
Knockout Mice
Cerebral Cortex
Epilepsy
Ischemia
Injections
Brain

Keywords

  • Apoptosis
  • Brain injury
  • Epilepsy
  • Excitotoxin
  • Hippocampus
  • Neurons
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Morrison, R. S., Wenzel, H. J., Kinoshita, Y., Robbins, C. A., Donehower, L. A., & Schwartzkroin, P. A. (1996). Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. Journal of Neuroscience, 16(4), 1337-1345.

Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. / Morrison, Richard S.; Wenzel, H. Jurgen; Kinoshita, Yoshito; Robbins, Carol A.; Donehower, Larry A.; Schwartzkroin, Philip A.

In: Journal of Neuroscience, Vol. 16, No. 4, 15.02.1996, p. 1337-1345.

Research output: Contribution to journalArticle

Morrison, RS, Wenzel, HJ, Kinoshita, Y, Robbins, CA, Donehower, LA & Schwartzkroin, PA 1996, 'Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death', Journal of Neuroscience, vol. 16, no. 4, pp. 1337-1345.
Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA. Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. Journal of Neuroscience. 1996 Feb 15;16(4):1337-1345.
Morrison, Richard S. ; Wenzel, H. Jurgen ; Kinoshita, Yoshito ; Robbins, Carol A. ; Donehower, Larry A. ; Schwartzkroin, Philip A. / Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. In: Journal of Neuroscience. 1996 ; Vol. 16, No. 4. pp. 1337-1345.
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