Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1(G93A) mice.
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.
Pardo
Andrea C
AC
Department of Neurology, Johns Hopkins University, 600 N. Wolfe St., Meyer 6-119, Baltimore, MD 21287, USA.
Wong
Victor
V
Benson
Leah M
LM
Dykes
Margaret
M
Tanaka
Kohichi
K
Rothstein
Jeffrey D
JD
Maragakis
Nicholas J
NJ
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*
D027322:Amino Acid Transport System X-AG; D027341:Excitatory Amino Acid Transporter 1; D013482:Superoxide Dismutase