TY - JOUR
T1 - Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1G93A mice
AU - Pardo, Andrea C.
AU - Wong, Victor
AU - Benson, Leah M.
AU - Dykes, Margaret
AU - Tanaka, Kohichi
AU - Rothstein, Jeffrey D.
AU - Maragakis, Nicholas J.
N1 - Funding Information:
This study was supported by the ALS Association, the Packard Center for ALS Research at Johns Hopkins, and NIH RO1NS041680.
PY - 2006/9
Y1 - 2006/9
N2 - 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 SOD1G93A mouse. In order to address this possible astrocyte-specific influence, we crossed the SOD1G93A 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 (SOD1G93A/GLT1±) exhibited an increase in the rate of motor decline accompanied by earlier motor neuron loss when compared with SOD1G93A 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 SOD1G93A/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.
AB - 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 SOD1G93A mouse. In order to address this possible astrocyte-specific influence, we crossed the SOD1G93A 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 (SOD1G93A/GLT1±) exhibited an increase in the rate of motor decline accompanied by earlier motor neuron loss when compared with SOD1G93A 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 SOD1G93A/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.
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U2 - 10.1016/j.expneurol.2006.03.028
DO - 10.1016/j.expneurol.2006.03.028
M3 - Article
C2 - 16753145
AN - SCOPUS:33747101645
SN - 0014-4886
VL - 201
SP - 120
EP - 130
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -