title: Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1(G93A) mice.
abstract: Recent studies have highlighted the role of astrocytes in the development of motor neuron disease in animal models. The astrocyte glutamate transporter GLT1 is responsible for a significant portion of glutamate transport from the synaptic cleft; regulating synaptic transmission and preventing glutamate excitotoxicity. While previous studies have demonstrated reductions in GLT1 with SOD1-mediated disease progression, it is not well established whether a reduction in this astrocyte-specific transporter alters the pathobiology of motor neuron degeneration in the SOD1(G93A) mouse. In order to address this possible astrocyte-specific influence, we crossed the SOD1(G93A) mouse line with a mouse heterozygous for GLT1 (GLT1+/-) exhibiting a significant reduction in transporter protein. Mice that carried both the SOD1 mutation and a reduced amount of GLT1 (SOD1(G93A)/GLT1+/-) exhibited an increase in the rate of motor decline accompanied by earlier motor neuron loss when compared with SOD1(G93A) mice. A modest reduction in survival was also noted in these mice. Dramatic losses of the GLT1 protein and reduced glutamate transport in the lumbar spinal cords of the SOD1(G93A)/GLT1+/- animals were also observed. GLT1 was not significantly changed in cortices from these animals suggesting that the effect of mutant SOD1 on GLT1 production/function was largely targeted to spinal cord rather than cortical astrocytes. This study suggests that astrocytes, and the astrocyte glutamate transporter GLT1, play a role in modifying disease progression and motor neuron loss in this model.
authors.affiliation: Department of Neurology, Johns Hopkins University, 600 N. Wolfe St., Meyer 6-119, Baltimore, MD 21287, USA.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Pardo
authors.forename: Victor
authors.initials: V
authors.lastname: Wong
authors.forename: Leah M
authors.initials: LM
authors.lastname: Benson
authors.forename: Margaret
authors.initials: M
authors.lastname: Dykes
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000870:Anterior Horn Cells / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D008161:Lumbosacral Region; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D027322:Amino Acid Transport System X-AG; D027341:Excitatory Amino Acid Transporter 1; D013482:Superoxide Dismutase