Systems NeuroscienceResearch PaperAltered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease
Section snippets
Animals
R6/1 hemizygote males (Jackson Laboratory, Bar Harbor, ME, USA) were bred with CBB6 (CBA×C 57/B6) F1 females to establish the R6/1 colony at the Howard Florey Institute. The CAG repeats length of transgenic mice in the colony at the time of cohort generation was in the range 127–135 (Pathology Department, University of Melbourne, Melbourne, Australia). Offspring were polymerase chain reaction (PCR) genotyped with genomic DNA obtained from toe biopsies. Mice were group housed in mixed-genotypes
Acute cannabinoid drug treatment results in behavioural consequences in R6/1 mice at 12 weeks of age
A single acute dose of cannabinoid partial agonist THC or vehicle was administered to female WT (n=7) and R6/1 (n=4) littermates 2.5 h prior to a tail suspension test. Within treatment groups, there was no difference between genotypes in time spent immobile. THC-treatment caused a significant increase in immobility for both WT (P<0.001) and R6/1 (P<0.001) mice compared to vehicle-treated counterparts.
CB1 receptor mRNA is decreased in the striatum but unchanged in the hippocampus and motor cortex of R6/1 mice at 12 weeks of age
In situ hybridisation of DNA probes was carried out on coronal brain sections from R6/1 HD mice
Discussion
A full characterisation of the cannabinoid system and other similarly distributed neurotransmitter receptors in R6/1 mice at 12 weeks of age is valuable for understanding HD disease pathogenesis prior to onset of behavioural symptoms. In this study, behavioural, mRNA, protein and ligand binding results demonstrate that CB1 is present and active at 12 weeks of age although regional, selective changes in the cannabinoid system are occurring.
The R6/1 model is a well-characterised model of HD, with
Acknowledgments
We thank L. Schwarcz for critical reading of this manuscript and J. Bullock for assistance with tissue processing. This work was supported by grants from the Neurological Foundation of New Zealand (M.G. and R.L.M.F.), the Australian National Health and Medical Research Council (A.J.H.) and a University of Auckland Health Research Doctoral Scholarship (M.J.D.).
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