Experience modulates the effects of histone deacetylase inhibitors on gene and protein expression in the hippocampus: Impaired plasticity in aging

The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with <300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specific mRNAs, gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus. Twenty-eight young (7 months old) male Fischer 344 × Brown Norway F1 hybrid rats (F344xBN) were divided into four groups (N=7/group) with three hippocampal subregions (CA1, CA3, and DG) queried, for a total of 84 microarray samples. Home cage controls were compared to animals receiving a single session of a redundant place-cue (RPC) variant of the water maze as an inducing event for examining hippocampal mRNA just prior to sacrifice (a week after basic water maze training for these animals). Animals were treated either with vehicle (100% DMSO) or the histone deacetylase inhibitor SAHA (50 mg/kg, delivered as 50 mg/ml i.p.) prior to any RPC-treatment, and 90 minutes prior to sacrifice for all animals.