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Impaired glutamate uptake in the R6 Huntington's disease transgenic mice
J C Liévens1, B Woodman, A Mahal
1Medical and Molecular Genetics, GKT School of Medicine, London, UK.
Insights
Huntington's disease (HD) involves CAG repeat expansion, leading to neuronal dysfunction. This study shows reduced glutamate transporter GLT1 in R6 mice, suggesting impaired glutamate uptake contributes to HD progression.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a late-onset neurodegenerative disorder caused by CAG/polyglutamine repeat expansion.
- R6 mouse models exhibit movement disorders and neuronal polyglutamine aggregates preceding selective cell death.
Purpose of the Study:
- To investigate the role of glutamate transporters in the R6 mouse model of Huntington's disease.
- To determine if altered glutamate uptake contributes to the HD phenotype.
Main Methods:
- Analysis of mRNA levels for astroglial glutamate transporters (GLT1, GLAST) and EAAC1 in R6 mice.
- Measurement of glutamate uptake in the striatum and cortex.
- Assessment of glutamine synthetase mRNA levels.
Main Results:
- A significant decrease in GLT1 mRNA and glutamate uptake was observed in the striatum and cortex of R6 mice.
- GLAST and EAAC1 expression remained unchanged.
- A decrease in astroglial glutamine synthetase mRNA was also detected prior to neurodegeneration.
Conclusions:
- Impaired astrocytic glutamate uptake, specifically via GLT1, may contribute to neuronal dysfunction and cell death in Huntington's disease.
- These molecular changes precede overt neurodegeneration, highlighting early pathological mechanisms in HD.
Abstract:
Huntington's disease (HD) is a late-onset neurodegenerative disease for which the mutation is CAG/polyglutamine repeat expansion. The R6 mouse lines expressing the HD mutation develop a movement disorder that is preceded by the formation of neuronal polyglutamine aggregates. The phenotype is likely caused by a widespread neuronal dysfunction, whereas neuronal cell death occurs late and is very selective. We show that a decreased mRNA level of the major astroglial glutamate transporter (GLT1) in the striatum and cortex of 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 synthetase is also decreased. These changes in expression occur prior to any evidence of neurodegeneration and suggest that a defect in astrocytic glutamate uptake may contribute to the phenotype and neuronal cell death in HD.
