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Journal of Neuroscience, Vol 5, 1483-1489, Copyright © 1985 by Society for Neuroscience
The neurotoxicity of excitatory amino acids is produced by passive chloride influx
SM Rothman
In the 15 years since the neurotoxic properties of glutamate and related
amino acids were first described, there has been no thoroughly convincing
explanation of the pathophysiology of excitatory amino acid- induced
neuronal death. These substances depolarize central neurons, increase the
frequency of neuronal discharge, and augment synaptic activity, leading to
the suggestion that one or more of these properties may in some way be
responsible for toxicity. More recently, an excessive calcium influx
triggered by amino acids has been implicated in this process. As isolation
of the different factors potentially involved in amino acid neurotoxicity
is virtually impossible in vivo, dispersed hippocampal cultures were used
to define the pathophysiology of this process in vitro. The toxicity of
glutamate, N-methyl-D-aspartate, and kainate was unaffected when calcium
was deleted and tetrodotoxin added to the balanced salt solution bathing
the cultures. In parallel experiments, the calcium ionophore A23187 was not
toxic in the presence of calcium. These experiments failed to confirm a
role for neuronal activity or calcium influx in this process. However, when
depolarization was blocked by deleting sodium from the control salt
solution, neither glutamate, N- methyl-D-aspartate, nor kainate produced
obvious changes. Alternately, when passive chloride influx was prevented by
largely deleting chloride from the bath, the cells were also unchanged by
the amino acids. Further experiments showed that depolarization produced by
high external potassium concentrations or veratridine was also toxic, but
only in the presence of external chloride. These experiments suggest that
the pathophysiology of amino acid neurotoxicity may be rather
straightforward.(ABSTRACT TRUNCATED AT 250 WORDS)
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