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Journal of Neuroscience, Vol 15, 4545-4555, Copyright © 1995 by Society for Neuroscience
Glia modulate the response of murine cortical neurons to excitotoxicity: glia exacerbate AMPA neurotoxicity
LL Dugan, VM Bruno, SM Amagasu and RG Giffard
Department of Anesthesia, Stanford University School of Medicine, California 94305, USA.
We have developed "pure" neuronal cultures (< 1% astrocytes) from mouse
neocortex to study the effect of glial cells on the response of neurons to
injury. Cortical neurons were found to require glial-conditioned medium to
survive. Immature neurons, 2-4 d in vitro, deprived of glial- conditioned
medium, underwent apoptosis over 48 hr, as suggested by condensed nuclear
morphology, DNA fragmentation, and protection by inhibition of
macromolecular synthesis. Apoptosis induced by trophic factor deprivation
has been described for other neuronal populations, such as superior
cervical ganglion and dorsal root ganglion cells. Cortical neurons in pure
culture provide another neuronal population for the study of apoptosis
induced by trophic factor deprivation. We then studied the interaction of
neurons and glia under excitotoxic conditions. Experiments on mature
cultures showed that pure neuronal cultures were at least 10-fold more
sensitive to acute glutamate exposure than were neuronal-glial ("mixed")
cocultures. The difference in sensitivity between pure neurons and mixed
cultures was reduced when mixed cultures were treated with the glutamate
uptake inhibitor, L- trans-pyrrolidine-2,4-dicarboxylic acid (trans-PDC).
In 24 hr exposure to N-methyl-D-aspartate (NMDA), or oxygen, glucose
deprivation, pure neurons were more sensitive than mixed cultures;
trans-PDC again increased the sensitivity of mixed cultures to nearly that
of pure neuronal cultures. In contrast, mixed and pure neuronal cultures
exposed to NMDA for 10 min, or to kainate for 24 hr, had similar injury
dose-response curves, suggesting that glial glutamate uptake is a less
important protective mechanism in these excitotoxic injuries. Surprisingly,
pure neurons were less sensitive than mixed cultures to
(RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) toxicity at
concentrations up to 100 microM. This does not reflect astrocyte toxicity,
as AMPA at concentrations to 1 mM did not injure astrocyte cultures. Glial
cultures showed increased levels of glutamate in the extracellular medium
in response to exposure to AMPA, but not NMDA or kainate. However, pure
neuronal and mixed cultures exposed to the same concentration of AMPA did
not have elevated levels of glutamate in the media. We found that glia were
generally neuroprotective under excitotoxic conditions, likely through
their ability to clear extracellular glutamate. However, the presence of
glia exacerbated AMPA neurotoxicity.
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