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Characterization of Excitatory Amino Acid Neurotoxicity in N ‐methyl‐D‐aspartate Receptor‐deficient Mouse Cortical Neuronal Cells
Author(s) -
Tokita Yoshihito,
Bessho Yasumasa,
Masu Masayuki,
Nakamura Kenji,
Nakao Kazuki,
Katsuki Motoya,
Nakanishi Shigetada
Publication year - 1996
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.1996.tb01168.x
Subject(s) - nmda receptor , kainate receptor , ampa receptor , neurotoxicity , glutamate receptor , receptor , biology , excitotoxicity , microbiology and biotechnology , long term depression , kainic acid , neuroscience , chemistry , pharmacology , biochemistry , toxicity , organic chemistry
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 α‐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 effectivein 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 were 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.