Presymptomatic glutamate levels in prefrontal cortex in the Hdh(CAG150) mouse model of Huntington's disease.

Abstract

Huntington's disease (HD) is a genetic neurodegenerative disorder with few available treatments. Clinical observations suggest prefrontal dysfunction in early stages of HD is associated with altered glutamate transport. Evidence from the R6/2 mouse model suggests an abnormal increase in glutamate signaling in the sensorimotor cortex and striatum. The present study was designed to determine if a similar deficit in glutamate function occurs in the prefrontal cortex (PFC) of Hdh(CAG150) mice. We used the following groups of 40 week old male and female Hdh(CAG150) mice: homozygote n = 7, heterozygote n = 7, wild type n = 6. Motor coordination was evaluated using a hanging wire grid test and a balance beam. Microdialysis measurements were taken from the PFC of freely moving mice while glutamate transporters were inhibited by L-trans-pyrrolidine-2, 4-dicarboxylate (PDC) and compared to baseline glutamate levels. RESULTS indicated an elevation in glutamate levels in response to PDC but no significant difference among genotype groups. When comparing wild type and homozygote alone, a significant difference in total extracellular glutamate was observed. Contrary to our original hypothesis, the homozygote group had lower glutamate levels compared to their wild type counterparts. Furthermore, there was a significant difference in GABA measurements across genotypes. Our results suggest a mechanistic dichotomy between R6/2 and Hdh(CAG150) mice and underscores the need to select the appropriate HD mouse model when assessing therapeutic interventions. In particular, the time when animals are evaluated can have a significant impact on behavioral and physiological measures and so should be carefully considered.