Decreased expression of GLT-1 in the R6/2 model of Huntington's disease does not worsen disease progression

Geraldine T. Petr, Laurel A. Schultheis, Kayla C. Hussey, Yan Sun, Janet M. Dubinsky, Chiye Aoki, Paul A. Rosenberg

Research output: Contribution to journalArticle

Abstract

Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease (HD). Glutamate is the predominant excitatory neurotransmitter in the brain, and excess activation of glutamate receptors can cause neuronal dysfunction and death. Glutamate transporters regulate the extracellular concentration of glutamate. GLT-1 is the most abundant glutamate transporter, and accounts for most of the glutamate transport in the brain. Administration of ceftriaxone, an antibiotic that increases the functional expression of GLT-1, can improve the behavioral phenotype of the R6/2 mouse model of HD. To test the hypothesis that GLT-1 expression critically affects the HD disease process, we generated a novel mouse model that is heterozygous for the null allele of GLT-1 and carries the R6/2 transgene (double mutation). We demonstrated that the protein expression of total GLT-1, as well as two of its isoforms, is decreased within the cortex and striatum of 12-week-old R6/2 mice, and that the expression of EAAC1 was decreased in the striatum. Protein expression of GLT-1 was further decreased in the cortex and striatum of the double mutation mice compared with the R6/2 mice at 11 weeks. However, the effects of the R6/2 transgene on weight loss, accelerating rotarod, climbing and paw-clasping were not exacerbated in these double mutants. Na+-dependent glutamate uptake into synapatosomes isolated from the striatum and cortex of 11-week-old R6/2 mice was unchanged compared with controls. These results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate the progression of HD. Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease (HD). Glutamate is the predominant excitatory neurotransmitter in the brain and excess activation of glutamate receptors can cause neuronal dysfunction and death. GLT-1 is the most abundant glutamate transporter, and here we show it is expressed in both excitatory terminals and astrocytes in the striatum. Our results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate HD progression.

Original languageEnglish (US)
Pages (from-to)2477-2490
Number of pages14
JournalEuropean Journal of Neuroscience
Volume38
Issue number3
DOIs
StatePublished - Aug 2013

Fingerprint

Huntington Disease
Disease Progression
Glutamic Acid
Amino Acid Transport System X-AG
Glutamate Receptors
Transgenes
Neurotransmitter Agents
Brain
Mutation
Ceftriaxone
Astrocytes
Weight Loss
Protein Isoforms
Proteins
Alleles
Anti-Bacterial Agents
Phenotype

Keywords

  • EM-ICC
  • Glutamate transporter
  • Na-dependent glutamate uptake
  • R6/2
  • Synaptosomes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Petr, G. T., Schultheis, L. A., Hussey, K. C., Sun, Y., Dubinsky, J. M., Aoki, C., & Rosenberg, P. A. (2013). Decreased expression of GLT-1 in the R6/2 model of Huntington's disease does not worsen disease progression. European Journal of Neuroscience, 38(3), 2477-2490. https://doi.org/10.1111/ejn.12202

Decreased expression of GLT-1 in the R6/2 model of Huntington's disease does not worsen disease progression. / Petr, Geraldine T.; Schultheis, Laurel A.; Hussey, Kayla C.; Sun, Yan; Dubinsky, Janet M.; Aoki, Chiye; Rosenberg, Paul A.

In: European Journal of Neuroscience, Vol. 38, No. 3, 08.2013, p. 2477-2490.

Research output: Contribution to journalArticle

Petr, Geraldine T. ; Schultheis, Laurel A. ; Hussey, Kayla C. ; Sun, Yan ; Dubinsky, Janet M. ; Aoki, Chiye ; Rosenberg, Paul A. / Decreased expression of GLT-1 in the R6/2 model of Huntington's disease does not worsen disease progression. In: European Journal of Neuroscience. 2013 ; Vol. 38, No. 3. pp. 2477-2490.
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