Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1G93A 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 SOD I-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 SODIG93A mouse. In order to address this possible astrocyte-specific influence, we crossed the SODIG93A 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 GLTI (SODIG93A/GLT1 +/-) exhibited an increase in the rate of motor decline accompanied by earlier motor neuron loss when compared with SODIG93A mice. A modest reduction in survival was also noted in these mice. Dramatic losses of the GLTI protein and reduced glutamate transport in the lumbar spinal cords of the SOD1(G93A)/GLTI +/- animals were also observed. GLT1 was not significantly changed in cortices from these animals suggesting that the effect of mutant SOD1 on GLTI production/function was largely targeted to spinal cord rather than cortical astrocytes. This study suggests that astrocytes, and the astrocyte glutamate transporter GLTI, play a role in modifying disease progression and motor neuron loss in this model. (c) 2006 Elsevier Inc. All rights reserved.