title: Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate.
abstract: Three glutamate transporters have been identified in rat, including astroglial transporters GLAST and GLT-1 and a neuronal transporter EAAC1. Here we demonstrate that inhibition of the synthesis of each glutamate transporter subtype using chronic antisense oligonucleotide administration, in vitro and in vivo, selectively and specifically reduced the protein expression and function of glutamate transporters. The loss of glial glutamate transporters GLAST or GLT-1 produced elevated extracellular glutamate levels, neurodegeneration characteristic of excitotoxicity, and a progressive paralysis. The loss of the neuronal glutamate transporter EAAC1 did not elevate extracellular glutamate in the striatum but did produce mild neurotoxicity and resulted in epilepsy. These studies suggest that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: M
authors.initials: M
authors.lastname: Dykes-Hoberg
authors.forename: C A
authors.initials: CA
authors.lastname: Pardo
authors.forename: L A
authors.initials: LA
authors.lastname: Bristol
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: R W
authors.initials: RW
authors.lastname: Kuncl
authors.forename: Y
authors.initials: Y
authors.lastname: Kanai
authors.forename: M A
authors.initials: MA
authors.lastname: Hediger
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J P
authors.initials: JP
authors.lastname: Schielke
authors.forename: D F
authors.initials: DF
authors.lastname: Welty
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression; D005971:Glutamates / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D005971:Glutamates; D016376:Oligonucleotides, Antisense