TY - JOUR
T1 - Dearth of glutamate transporters contributes to striatal excitotoxicity
AU - Brustovetsky, Tatiana
AU - Purl, Kevin
AU - Young, Anisa
AU - Shimizu, Kazuyuki
AU - Dubinsky, Janet M.
PY - 2004/10
Y1 - 2004/10
N2 - 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 EAAC1and 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.
AB - 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 EAAC1and 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.
KW - Anionic liposomes
KW - EAAC1
KW - GLAST
KW - GLT1
KW - Glutamate transporters
KW - Huntington's disease
KW - Neurodegeneration
KW - Selective vulnerability
UR - http://www.scopus.com/inward/record.url?scp=4544225524&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4544225524&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2004.03.021
DO - 10.1016/j.expneurol.2004.03.021
M3 - Article
C2 - 15380474
AN - SCOPUS:4544225524
SN - 0014-4886
VL - 189
SP - 222
EP - 230
JO - Neurodegeneration
JF - Neurodegeneration
IS - 2
ER -