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

Antigone Wolfram-Aduan, Megan Altemus, John H. Wickwire, Michael I. Sandstrom

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: 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. Objective: The present study was designed to determine if a similar deficit in glutamate function occurs in the prefrontal cortex (PFC) of Hdh(CAG150) mice. Methods: 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: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)387-399
Number of pages13
JournalJournal of Huntington's Disease
Volume3
Issue number4
DOIs
StatePublished - 2014

Keywords

  • Hdh
  • Huntington's disease
  • animal models
  • microdialysis
  • prefrontal cortex

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