PMID:8713451

Citation	Tokita, Y, Bessho, Y, Masu, M, Nakamura, K, Nakao, K, Katsuki, M and Nakanishi, S (1996) Characterization of excitatory amino acid neurotoxicity in N-methyl-D-aspartate receptor-deficient mouse cortical neuronal cells. Eur. J. Neurosci. 8:69-78
Abstract	Roles and mechanisms of N-methyl-D-aspartate (NMDA) receptors in glutamate neurotoxicity were investigated in cultures of NMDA receptor-deficient cortical neuronal cells. Mutant mice lacking a functional NMDA receptor were generated by gene targeting of the NR1 NMDA receptor subunit. Cortical neuronal cells prepared from wild-type NR1+/+, heterozygous NR1+/- and homozygous mutant NR1-/- mice at 15-17 days of gestation grew indistinguishably from each other. Brief exposures (5 min) of both NR1+/+ and NR1+/- neuronal cells to glutamate or NMDA, but not kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), resulted in widespread neuronal degeneration by the following day. In contrast, neither glutamate nor NMDA treatment caused neuronal degeneration in NR1-/- cells, indicating that NMDA receptors are responsible for rapidly triggered glutamate neurotoxicity. The above four compounds were all effective in inducing the death of NR1+/+ and NR1+/- neuronal cells after prolonged exposure (20-24 h). However, NMDA had no neurotoxic effects on NR1-/- cells, although the other three compounds wer neurotoxic with potencies comparable to those for NR1+/+ and NR1+/- cells. The AMPA and kainate receptors are thus sufficient for inducing slowly triggered glutamate neurotoxicity. Brief exposure of a mixed population of NR1+/+ and NR1-/- neuronal cells to NMDA selectively killed the NMDA receptor-expressing cells without any appreciable effects on neighbouring NMDA receptor-deficient cells. This finding further supports a direct and indispensable role for NMDA receptors in NMDA-evoked neuronal cell death.
Links	PubMed
Keywords	Animals; Cell Survival/drug effects; Cells, Cultured; Cerebral Cortex/drug effects; Cerebral Cortex/pathology; Cerebral Cortex/physiology; Chimera; Female; Glutamic Acid/toxicity; Membrane Potentials/drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Neurologic Mutants; N-Methylaspartate/toxicity; Neurons/drug effects; Neurons/pathology; Neurons/physiology; Neurotoxins/toxicity; Receptors, AMPA/physiology; Receptors, Kainic Acid/physiology; Receptors, N-Methyl-D-Aspartate/genetics; Receptors, N-Methyl-D-Aspartate/physiology; Stem Cells; Transfection
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