Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1G93A mice

Andrea C. Pardo, Victor Wong, Leah M. Benson, Margaret Dykes, Kohichi Tanaka, Jeffrey D. Rothstein, Nicholas J. Maragakis*

*Corresponding author for this work

Research output: Contribution to journalArticle

77 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)120-130
Number of pages11
JournalExperimental Neurology
Volume201
Issue number1
DOIs
StatePublished - Sep 2006

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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    Pardo, A. C., Wong, V., Benson, L. M., Dykes, M., Tanaka, K., Rothstein, J. D., & Maragakis, N. J. (2006). Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1G93A mice. Experimental Neurology, 201(1), 120-130. https://doi.org/10.1016/j.expneurol.2006.03.028