Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative 
disorder caused by an expansion of a CAG/polyglutamine repeat for which there 
are no disease modifying treatments. In recent years, transcriptional 
dysregulation has emerged as a pathogenic process that appears early in disease 
progression and has been recapitulated across multiple HD models. Altered 
histone acetylation has been proposed to underlie this transcriptional 
dysregulation and histone deacetylase (HDAC) inhibitors, such as suberoylanilide 
hydroxamic acid (SAHA), have been shown to improve polyglutamine-dependent 
phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as 
SAHA display toxic side-effects. To better understand the mechanism underlying 
this potential therapeutic benefit and to dissociate the beneficial and toxic 
effects of SAHA, we set out to identify the specific HDAC(s) involved in this 
process. For this purpose, we are exploring the effect of the genetic reduction 
of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The 
study presented here focuses on HDAC3, which, as a class I HDAC, is one of the 
preferred targets of SAHA and is directly involved in histone deacetylation. To 
evaluate a potential benefit of Hdac3 genetic reduction in R6/2, we generated a 
mouse carrying a critical deletion in the Hdac3 gene. We confirmed that the 
complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 
inhibition, we used Hdac3(+/-) heterozygotes to reduce nuclear HDAC3 levels in 
R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiological or 
behavioural phenotypes and has no effect on molecular changes including 
dysregulated transcripts. We conclude that HDAC3 should not be considered as the 
major mediator of the beneficial effect induced by SAHA and other HDAC 
inhibitors in HD.