Dearth of glutamate transporters contributes to striatal excitotoxicity.
Since excitotoxicity is hypothesized to contribute to cell death in Huntington's disease (HD), we examined the susceptibility of striatal and hippocampal neurons to glutamate-induced cell death. Striatal cultures were more susceptible to glutamate-triggered toxicity than sister hippocampal cultures. Dose-response curves were equivalent when secondary toxicity was blocked with application of the NMDA receptor antagonist, MK801, or enhanced with the pan-specific glutamate transport blocker, TBOA, following excitotoxin removal. TBOA failed to alter the dose-response characteristics of striatal excitotoxicity, ruling out reverse operation of glutamate transporters. Striatal cultures expressed less EAAC1 and less membrane-associated EAAC1, GLT1, and GLAST than hippocampal cultures. Antisense down-regulation of EAAC1 increased the sensitivity of hippocampal cultures to glutamate, indicating that this transporter can act as an important neuroprotectant. Thus, the relative expression levels of glutamate transporters, even in parts of the brain where they are considered adequately expressed, appear to influence the sensitivities of different neuronal populations to excitotoxicity.
Brustovetsky
Tatiana
T
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Purl
Kevin
K
Young
Anisa
A
Shimizu
Kazuyuki
K
Dubinsky
Janet M
JM
D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D027981:Symporters / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D016375:Antisense Elements (Genetics); D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D009498:Neurotoxins; D027981:Symporters; D018698:Glutamic Acid