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 known 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, are 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 to the R6/2 mice at 11 weeks of age. 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 to controls. These results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate the progression of HD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.