Evidence for p53-mediated modulation of neuronal viability

Hong Xiang, Daryl W. Hochman, Hideyuki Saya, Toshiyoshi Fujiwara, Philip A. Schwartzkroin, Richard S. Morrison

Research output: Contribution to journalArticle

219 Citations (Scopus)

Abstract

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 knockout 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.

Original languageEnglish
Pages (from-to)6753-6765
Number of pages13
JournalJournal of Neuroscience
Volume16
Issue number21
Publication statusPublished - 1996 Nov 1
Externally publishedYes

Fingerprint

Neurons
Neurotoxins
Knockout Mice
Glutamic Acid
Calcium
Intermediate Filaments
Propidium
Kainic Acid
Adenoviridae
Brain Injuries
Epilepsy
Hippocampus
Seizures
Cell Death
Ischemia
Staining and Labeling
DNA
Brain

Keywords

  • adenovirus
  • apoptosis
  • brain injury
  • Ca
  • epilepsy
  • excitotoxin
  • hippocampus
  • neurons
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Xiang, H., Hochman, D. W., Saya, H., Fujiwara, T., Schwartzkroin, P. A., & Morrison, R. S. (1996). Evidence for p53-mediated modulation of neuronal viability. Journal of Neuroscience, 16(21), 6753-6765.

Evidence for p53-mediated modulation of neuronal viability. / Xiang, Hong; Hochman, Daryl W.; Saya, Hideyuki; Fujiwara, Toshiyoshi; Schwartzkroin, Philip A.; Morrison, Richard S.

In: Journal of Neuroscience, Vol. 16, No. 21, 01.11.1996, p. 6753-6765.

Research output: Contribution to journalArticle

Xiang, H, Hochman, DW, Saya, H, Fujiwara, T, Schwartzkroin, PA & Morrison, RS 1996, 'Evidence for p53-mediated modulation of neuronal viability', Journal of Neuroscience, vol. 16, no. 21, pp. 6753-6765.
Xiang H, Hochman DW, Saya H, Fujiwara T, Schwartzkroin PA, Morrison RS. Evidence for p53-mediated modulation of neuronal viability. Journal of Neuroscience. 1996 Nov 1;16(21):6753-6765.
Xiang, Hong ; Hochman, Daryl W. ; Saya, Hideyuki ; Fujiwara, Toshiyoshi ; Schwartzkroin, Philip A. ; Morrison, Richard S. / Evidence for p53-mediated modulation of neuronal viability. In: Journal of Neuroscience. 1996 ; Vol. 16, No. 21. pp. 6753-6765.
@article{c69214039ef84b1abf120b57de023b6e,
title = "Evidence for p53-mediated modulation of neuronal viability",
abstract = "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 knockout 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.",
keywords = "adenovirus, apoptosis, brain injury, Ca, epilepsy, excitotoxin, hippocampus, neurons, p53",
author = "Hong Xiang and Hochman, {Daryl W.} and Hideyuki Saya and Toshiyoshi Fujiwara and Schwartzkroin, {Philip A.} and Morrison, {Richard S.}",
year = "1996",
month = "11",
day = "1",
language = "English",
volume = "16",
pages = "6753--6765",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "21",

}

TY - JOUR

T1 - Evidence for p53-mediated modulation of neuronal viability

AU - Xiang, Hong

AU - Hochman, Daryl W.

AU - Saya, Hideyuki

AU - Fujiwara, Toshiyoshi

AU - Schwartzkroin, Philip A.

AU - Morrison, Richard S.

PY - 1996/11/1

Y1 - 1996/11/1

N2 - 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 knockout 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.

AB - 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 knockout 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.

KW - adenovirus

KW - apoptosis

KW - brain injury

KW - Ca

KW - epilepsy

KW - excitotoxin

KW - hippocampus

KW - neurons

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=0029910961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029910961&partnerID=8YFLogxK

M3 - Article

VL - 16

SP - 6753

EP - 6765

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 21

ER -