Evidence for p53-Mediated Modulation of Neuronal Viability

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Volume 16, Number 21, Issue of November 1, 1996 pp. 6753-6765
Copyright ©1996 Society for Neuroscience

Evidence for p53-Mediated Modulation of Neuronal Viability

Received June 24, 1996; revised Aug. 12, 1996; accepted Aug. 20, 1996.
Hong Xiang¹, Daryl W. Hochman¹, Hideyuki Saya², Toshiyoshi Fujiwara³, Philip A. Schwartzkroin¹, and Richard S. Morrison¹
¹ Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington 98195-6470, ² Department of Oncology, Kumamoto University School of Medicine, Kumamoto 860, Japan, and ³ First Department of Surgery, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan
A 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. These findings were recently extended with the demonstration that mice deficient in p53 (``knock-out'' mice) exhibit almost complete protection from seizure-induced brain injury, whereas wild-type mice display significant neuronal cell loss in the hippocampus and other brain regions. Because the p53 knock-out mice used in the latter study expressed a global p53 deficiency in all cell types, it was not possible to conclude that protection was conferred by the exclusive absence of p53 in neurons. Therefore, in the present study, we determined whether p53 expression in isolated neurons is directly coupled to a loss of viability associated with excitotoxic challenge. Primary cultures of hippocampal or cortical neurons were derived from animals containing p53 (+/+, +/ $-$ ) or those deficient in p53 ( $-$ / $-$ ). p53-Deficient neurons appeared identical to wild-type neurons with respect to morphology, neurofilament expression, and resting levels of intracellular calcium. Neurons containing at least one copy of p53 were severely damaged by exposure to kainic acid or glutamate. Cell damage was assessed by direct cell counting and by nuclear morphology after propidium iodide staining of DNA. In contrast, neurons deficient in p53 ( $-$ / $-$ ) exhibited little or no damage in response to excitotoxin treatment. Despite their divergent outcomes, p53 (+/+) and p53 ( $-$ / $-$ ) neurons demonstrated similar sustained elevations in intracellular calcium levels triggered by glutamate exposure. Restoring p53 expression to p53-deficient neurons, using adenovirus-mediated transduction, was sufficient to promote neuronal cell death even in the absence of excitotoxin. These results demonstrate a direct relationship between p53 expression and loss of viability in CNS neurons.

Key words: p53; neurons; brain injury; epilepsy; apoptosis; hippocampus; excitotoxin; adenovirus; Ca²⁺

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