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The Journal of Neuroscience, March 15, 2001, 21(6):1876-1883

Antisense Knockdown of the Glial Glutamate Transporter GLT-1, But Not the Neuronal Glutamate Transporter EAAC1, Exacerbates Transient Focal Cerebral Ischemia-Induced Neuronal Damage in Rat Brain

Vemuganti L. Raghavendra Rao^{1, 2}, Aclan Dogan¹, Kathryn G. Todd⁴, Kellie K. Bowen¹, Bum-Tae Kim^{1, 5}, Jeffrey D. Rothstein⁶, and Robert J. Dempsey^{1, 3}

¹ Department of Neurological Surgery and ² Cardiovascular Research Center, University of Wisconsin-Madison, Madison, Wisconsin 53792, ³ William S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin 53792, ⁴ Department of Psychiatry, University of Alberta, Edmonton, Canada T6G 2B7, ⁵ Department of Neurosurgery, Soonchunhyang University Hospital, Seoul, Korea, and ⁶ Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Transient focal cerebral ischemia leads to extensive neuronal damage in cerebral cortex and striatum. Normal functioning of glutamate transporters clears the synaptically released glutamate to prevent excitotoxic neuronal death. This study evaluated the functional role of the glial (GLT-1) and neuronal (EAAC1) glutamate transporters in mediating ischemic neuronal damage after transient middle cerebral artery occlusion (MCAO). Transient MCAO in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) led to increased infarct volume (45 ± 8%; p < 0.05), worsened neurological status, and increased mortality rate, compared with GLT-1 sense/random ODN-infused controls. Transient MCAO in rats infused with EAAC1 antisense ODNs had no significant effect on any of these parameters. This study suggests that GLT-1, but not EAAC1, knockdown exacerbates the neuronal death and thus neurological deficit after stroke.

Key words: antisense knockdown; EAAC1; focal cerebral ischemia; GLT-1; glutamate transporters; middle cerebral artery occlusion; neuronal damage; stroke

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2161876-08$05.00/0

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