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Journal of Neuroscience, Vol 12, 773-780, Copyright © 1992 by Society for Neuroscience
Effects of excitotoxin exposure on metabolic rate of primary hippocampal cultures: application of silicon microphysiometry to neurobiology
KM Raley-Susman, KR Miller, JC Owicki and RM Sapolsky
Department of Biological Sciences, Stanford University, California 94305.
Increasing evidence implicates glutamate receptor over-stimulation in the
neurotoxicity associated with a host of metabolic insults, including
seizures and hypoxia-ischemia. To begin to understand more completely the
role of energy metabolism in the mechanism of neuron death following
excitatory amino acid exposure, we investigated the effects of kainic acid
exposure on metabolic rate in cultured hippocampal cells using a recently
developed silicon microphysiometer. The device gives a continual real-time
measure of metabolism in relatively small numbers of cells, as assessed by
efflux of protons generated at least in part by ATP hydrolysis and lactic
acid production. In the first half of this report, we characterize the
feasibility of using this device for measuring cellular metabolism in
hippocampal cultures. Metabolic rate in both astrocytes and neurons was
readily detectable, with a high signal-to-noise ratio. The rate was
proportional to the number of cells and was sensitive to metabolic
enhancement or depression. We then utilized this device to study metabolic
responses to the excitotoxin kainic acid. We observed a receptor-mediated,
dose-dependent increase in metabolic rate upon stimulation by kainic acid,
with an EC50 of approximately 100 microM. Exposure to toxic levels of
kainic acid for 10 min produced an initial elevation (for 2 hr) in
metabolic rate and then a gradual decline in metabolism over the next 8 hr
that preceded a measurable loss of cell viability. This study further
delineates a time window for the onset of kainic acid-induced damage. The
results clearly show the feasibility of using silicon microphysiometry for
assessing metabolism of brain cultures and for exploring the relationship
between metabolism and synaptic activation.
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