Differential Susceptibility to Neurotoxicity Mediated by Neurotrophins and Neuronal Nitric Oxide Synthase

NMDA neurotoxicity, which is mediated, in part, by formation of nitric oxide (NO) via activation of neuronal NO synthase (nNOS), is modulated by neurotrophins. nNOS expression in rat and mouse primary neuronal cultures grown on a glial feeder layer is significantly less than that of neurons grown on...

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Bibliographic Details
Published in:	The Journal of neuroscience Vol. 17; no. 12; pp. 4633 - 4641
Main Authors:	Samdani, Amer F, Newcamp, Cheryl, Resink, Annelies, Facchinetti, Fabrizio, Hoffman, Brian E, Dawson, Valina L, Dawson, Ted M
Format:	Journal Article
Language:	English
Published:	United States Soc Neuroscience 15-06-1997 Society for Neuroscience
Subjects:	Animals Arginine - pharmacology Brain-Derived Neurotrophic Factor - pharmacology Cell Survival - drug effects Cells, Cultured Cerebral Cortex - cytology Cerebral Cortex - embryology Coculture Techniques Embryo, Mammalian Fetus Gene Expression Regulation, Enzymologic - drug effects Glial Cell Line-Derived Neurotrophic Factor Kinetics Mice Mice, Inbred C57BL N-Methylaspartate - antagonists & inhibitors N-Methylaspartate - toxicity Nerve Growth Factors - pharmacology Nerve Tissue Proteins - pharmacology Neuroglia - physiology Neurons - cytology Neurons - drug effects Neurons - enzymology Neurotoxins Neurotrophin 3 NG-Nitroarginine Methyl Ester - pharmacology Nitric Oxide Synthase - biosynthesis Nitric Oxide Synthase - deficiency Nitric Oxide Synthase - metabolism Nitroprusside - pharmacology Peptides Rats Rats, Sprague-Dawley
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Summary:	NMDA neurotoxicity, which is mediated, in part, by formation of nitric oxide (NO) via activation of neuronal NO synthase (nNOS), is modulated by neurotrophins. nNOS expression in rat and mouse primary neuronal cultures grown on a glial feeder layer is significantly less than that of neurons grown on a polyornithine (Poly-O) matrix. Neurotrophins markedly increase the number of nNOS neurons, nNOS protein, and NOS catalytic activity and enhance NMDA neurotoxicity via NO-dependent mechanisms when neurons are grown on glial feeder layers. In contrast, when rat or mouse primary cortical neurons are grown on a Poly-O matrix, neurotrophins have no influence on nNOS neuronal number or NOS catalytic activity and reduce NMDA neurotoxicity. Primary neuronal cultures from mice lacking nNOS grown on a glial feeder layer fail to respond to neurotrophin-mediated enhancement of neurotoxicity. Together, these results indicate that nNOS expression and NMDA NO-mediated neurotoxicity are dependent, in part, on the culture paradigm, and neurotrophins regulate the susceptibility to NMDA neurotoxicity via modulation of nNOS. Furthermore, these results support the idea that NMDA neurotoxicity in culture is critically dependent on the developmental state of the neurons being assessed and suggest that, when cortical neurons are cultured on a glial feeder layer, they do not reach nearly as mature a phenotype as when grown on a Poly-O matrix.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0270-6474 1529-2401
DOI:	10.1523/jneurosci.17-12-04633.1997