Differential susceptibility to neurotoxicity mediated by neurotrophins and neuronal nitric oxide synthase

Amer F. Samdani, Cheryl Newcamp, Annelies Resink, Fabrizio Facchinetti, Brian E. Hoffman, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4633-4641
Number of pages9
JournalJournal of Neuroscience
Volume17
Issue number12
StatePublished - Jun 24 1997

Keywords

  • Excitotoxicity
  • Glutamate
  • Growth Factors
  • NMDA
  • Neurotrophins
  • Nitric oxide

ASJC Scopus subject areas

  • Neuroscience(all)

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