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Volume 17, Number 12,
Issue of June 15, 1997
pp. 4633-4641
Copyright ©1997 Society for Neuroscience
Differential Susceptibility to Neurotoxicity Mediated by
Neurotrophins and Neuronal Nitric Oxide Synthase
Received Jan. 22, 1997; revised March 21, 1997; accepted April 3, 1997.
Amer F. Samdani1,
Cheryl Newcamp1,
Annelies Resink1,
Fabrizio Facchinetti1,
Brian E. Hoffman1,
Valina L. Dawson1, 2, 3, and
Ted M. Dawson1, 2
Departments of 1 Neurology, 2 Neuroscience,
and 3 Physiology, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21287
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.
Key words:
neurotrophins;
growth factors;
excitotoxicity;
glutamate;
NMDA;
nitric oxide
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