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Journal of Neuroscience, Vol 16, 200-209, Copyright © 1996 by Society for Neuroscience
AMPA receptor activation is rapidly toxic to cortical astrocytes when desensitization is blocked
JC David, KA Yamada, MR Bagwe and MP Goldberg
Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Although cultured astrocytes express functional glutamate receptors, they
are generally resistant to excitotoxic cell death. We explored the role of
receptor desensitization in glutamate-mediated astrocyte injury. In
cultures of type 1 astrocytes from mouse neocortex, brief application of
AMPA evoked small, rapidly desensitizing inward currents, whereas kainate
evoked small, sustained currents. Neither agonist increased cytosolic
calcium, and astrocyte toxicity occurred only after 24 hr exposure to high
(500-1000 microM) concentrations of kainate but not to AMPA or glutamate.
Cyclothiazide, a drug that selectively blocks AMPA receptor
desensitization, greatly potentiated AMPA- or kainate-gated currents and
intracellular calcium elevation. Coapplication of 10-100 microM
cyclothiazide with glutamate, AMPA, or kainate produced widespread
astrocyte cell death within 2 hr or application. The enhancement of
toxicity by cyclothiazide, which alone was not toxic, was
concentration-dependent for each of the tested agonists (EC50 30-100
microM) and was blocked by further addition of the selective AMPA/kainate
antagonist 2,3-dioxo-6-nitro-7- sulfamoylbenzo(f)quinoxaline (NBQX). NMDA
caused no injury even in the presence of cyclothiazide.
Cyclothiazide-enhanced injury varied with the age of astrocyte cultures;
the maximal effect occurred at approximately 2 weeks in vitro, and little
death was seen after 4 weeks. Type 1 astrocytes express AMPA-type glutamate
receptors that are unmasked by reducing their desensitization with
cyclothiazide. Although overactivation of AMPA receptors can be rapidly
lethal to astrocytes, rapid desensitization normally limits this toxicity.
The extent of AMPA receptor desensitization may be an important determinant
of glial vulnerability to excitotoxic insults.
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