A02 Striatal procedural memory-induced transcriptome and epigenome are severely impaired in huntington’s disease mice

Background Huntington’s disease (HD) patients suffer from cognitive alterations involving striatal procedural learning and memory, preceding the onset of motor symptoms. However, underlying mechanisms remain poorly understood. In addition, specific transcriptional and epigenetic signatures characterize the striatum of HD patients and mouse models, but their relationship with cognitive impairment is unclear. Aims To develop a reliable behavioural task and assess striatal-dependent procedural learning and memory in HD mice and characterize transcriptional and epigenomic regulations participating in physiological and pathological cognitive processes. Methods We have adapted to mice a procedural task (the double-H maze) previously developed for rats, and tested control and R6/1 transgenic mice at early symptomatic stages. In parallel, we generated striatal transcriptomic (RNA-seq) and epigenomic (ChiP-seq) data using resting and behaving animals. Results R6/1 mice present an early impairment in striatal-dependent procedural learning and memory in the double-H task, preceding motor deficits, and accompanied by altered transcriptional regulation associated to learning and memory processes. Additionally, we profiled H3K27 acetylation (H3K27ac), H3K9 acetylation (H3K9ac) and RNA Polymerase II (RNAPII) using ChIP-seq on WT and R6/1 mouse striatum in basal state and during memory consolidation/recall. We observed a consistent depletion of H3K27ac, H3K9ac and RNAPII at striatal identity genes in R6/1 mice, strongly correlating with HD transcriptional alterations. Moreover, in WT mice striatum, H3K9ac was specifically modulated during memory process, and was notably implicated in the priming of myelin genes. Remarkably, this mechanism was deficient in R6/1 mice. Conclusions Our data highlight the role of epigenetic and transcriptional mechanisms in HD cognitive deficits, and provides a novel target, H3K9ac, as potential underlying mechanism.