ASO-mediated RNA Suppression through Targeted Epigenetic Reprogramming of the Hdac2 Gene

We elicited ASO-mediated knockdown of mRNAs in the nervous system by targeting the memory-repressor gene Histone deacetylase 2 (Hdac2) in vitro and in vivo. We observed that an Hdac2-targeted ASO not only triggered a reduction in mRNA levels, but also a direct transcriptional suppression of the Hdac2 gene in neurons in vitro. In further in vivo studies, we observed that a single dose of the Hdac2-targeted ASO delivered by intracerebroventricular injection into the central nervous system (CNS) achieved steady-state diminution of Hdac2 mRNA levels that lasted more than 6 months in vivo. Knockdown of this factor resulted in memory enhancement. ASO administration also caused a prolonged alteration of steady-state levels of a set of known memory-associated mRNAs and triggered secondary changes in the epigenome at sites outside of the primary target gene. Overall design: 3 scrambled ASO and 3 HDAC2 ASO mice were sacrificed and at 9 timepoints (3d, 2w, 4w, 8w, 16w, 32w, 40w, 48w, 52w) after ASO injection. Cortex, hippocampus and cerebellum were analyzed for total RNA expression. expression.