Impaired glutamate uptake in the R6 Huntington's disease transgenic mice

Huntington's disease (HD) is a late-onset neurodegenerative disease for whi ch the mutation is CAG/polyglutamine repeat expansion. The R6 mouse lines e xpressing the HD mutation develop a movement disorder that is preceded by t he formation of neuronal polyglutamine aggregates. The phenotype is likely caused by a widespread neuronal dysfunction, whereas neuronal cell death oc curs late and is very selective. We show that a decreased mRNA level of the major astroglial glutamate transporter (GLT1) in the striatum and cortex o f these mice is accompanied by a concomitant decrease in glutamate uptake. In contrast, the expression of the glutamate transporters, GLAST and EAAC1, remain unchanged. The mRNA level of the astroglial enzyme glutamine synthe tase is also decreased. These changes in expression occur prior to any evid ence of neurodegeneration and suggest that a defect in astrocytic glutamate uptake may contribute to the phenotype and neuronal cell death in HD. (C) 2001 Academic Press.