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Induced tolerance to glutamate neurotoxicity through down‐regulation of NR2 subunits of N‐methyl‐D‐aspartate receptors in cultured rat striatal neurons
Author(s) -
Kambe Yuki,
Nakamichi Noritaka,
Takarada Takeshi,
Fukumori Ryo,
Yoneda Yukio
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22388
Subject(s) - glutamate receptor , neurotoxicity , receptor , nmda receptor , chemistry , neuroscience , pharmacology , biology , microbiology and biotechnology , biochemistry , toxicity , organic chemistry
We have previously shown differential vulnerabilities to glutamate (Glu) excitotoxicity mediated by the N‐methyl‐D‐aspartate (NMDA) receptor (NMDAR) between rat cortical and rat hippocampal neurons in culture. In this study, we evaluated the possible induced tolerance to NMDA neurotoxicity in cultured rat striatal neurons with prior sustained activation of NMDAR. Brief exposure to Glu or NMDA for 1 hr led to a significant decrease in cellular vitality determined 24 hr later in cultured rat striatal neurons, whereas no marked loss was seen in cellular survival after exposure to Glu or NMDA in striatal neurons previously cultured with Glu or NMDA. Sustained culture with Glu or NMDA invariably led to a significant decrease in protein levels of NR2, but not NR1, subunits without affecting their mRNA levels. Similar induced tolerance was seen to the excitotoxicity of NMDA in hippocampal neurons in a manner sensitive to an NMDAR antagonist. Prior culture with NMDA induced less effective alterations in both intracellular free Ca 2+ levels and mitochondrial membrane potentials after the addition of NMDA in striatal neurons. However, calpain inhibitor‐I significantly prevented the decreased NR2B and NR2C protein levels in striatal neurons cultured with NMDA. These results suggest that prior tonic activation of NMDAR would induce tolerance to the excitotoxicity mediated by NMDAR through a mechanism related to calpain‐induced down‐regulation of particular NR2 subunits in rat striatal neurons. © 2010 Wiley‐Liss, Inc.