Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington’s disease transgenic mice

Loss of cannabinoid receptors (CB1) occurs prior to neurodegeneration in Huntington’s disease (HD). The levels and
distribution of CB1 RNA were equivalent in 3-week-old
mice regardless of genotype demonstrating that the specific
factors and appropriate chromatin structure that lead to the
transcription of CB1 were present in the striatum of young
R6/2 and R6/1 transgenic HD mice. The expression of the
mutant HD transgene led progressively to decreased steadystate levels of CB1 mRNA in neurons of the lateral striatum,
which was dependent on the size of the CAG repeat and
relative expression of the gene encoding mutant huntingtin
(HD). Although it is known that the coding region of CB1 is
contained within a single exon in mice, rats and humans, the
5¢-untranslated region of the mouse gene remained to be
defined. CB1 mRNA is encoded by two exons separated by
an 18.4-kb intron. Transcription of CB1 occurred at multiple
sites within a GC-rich promoter region upstream of exon 1
encoding the 5¢-UTR of CB1. There was no difference in the
selection of specific transcription initiation sites associated
with higher levels of CB1 expression in the striatum compared to the cortex or between the striata of wild-type and
HD transgenic mice. The progressive decline in CB1 mRNA
levels in R6 compared to wild-type mice was due to decreased
transcription, which is consistent with the hypothesis that
mutant huntingtin exerts its effects by altering transcription
factor activity. The cell-specific conditions that allow for
increased transcription of CB1 in the lateral striatum compared to other forebrain regions from all transcription start
sites were affected by the expression ofmutant huntingtinin a
time-dependent manner.