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Reduction of the transmembrane Na+ gradient is expected to induce neurotoxic glutamate release via reversed uptake. We describe neuronal death induced by lowering extracellular Na+ concentration in cultured rat hippocampal slices. When slices were exposed to 3.6 mM Na+ for 30 min, almost all the neurons in the CA1 region were degenerated within 20-24 h. The marginal concentration of external Na+ for induction of neurotoxicity was 6.6 mM. N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801 at 1-3 microM and (+/-)-CPP at 30 microM, significantly decreased these neurotoxic effects. A non-NMDA receptor antagonist, DNQX at 30-100 microM, had no protective effect against neurotoxicity. Removal of external Ca2+ completely eliminated neuronal death, but replacing external Cl- with SO4(2-) had no protective effect against neurotoxicity. A drastic 40-fold increase in glutamate release was produced by 30 min exposure to 3.6 mM Na+, and this release was partially independent of external Ca2+. These findings suggest that the low-Na(+)-induced neurotoxicity we observed is mediated by excessive release of glutamate via reversed uptake and subsequent Ca(2+)-influx through NMDA receptors. The model reported here may be useful for investigation of the mechanism of neuronal injury mediated by endogenous glutamate.

01 Aug 1996·Neuroscience ResearchQ4 · MEDICINE

Depolarization with high-K+ causes Cal2+-independent but partially Cl−-dependent glutamate release in rat hippocampal slice cultures

Q4 · MEDICINE

Article

Author: Takahashi, Masaru ; Hashimoto, Munehiro

We studied the neurotoxic glutamate release induced by high-K+ depolarization in rat hippocampal slice cultures. Depolarization with 90 mM K+ for 30 min caused a significant, three-fold increase in glutamate release. This release was not inhibited by removing extracellular Ca2+, but was significantly inhibited by replacement of extracellular Cl- with SO4(2-). These findings suggest that glutamate is released by mechanisms other than conventional vesicular release under the high-K+ condition.

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