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.组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor, HDACi）疗法的治疗潜力，在新兴的认知神经表观遗传学领域已受到广泛关注。然而，当下进行的认知活动可显著调控HDACi给药的细胞生物学效应这一可能性，尚未得到系统性研究。在针对该问题开展的初始实验中，我们探究了水迷宫训练是否会影响年轻成年大鼠海马体中，急性全身HDACi给药后的基因表达应答反应。结果显示，训练可强力调控HDACi治疗的应答反应：相较于仅接受HDACi给药时的不足300个调控基因，联合训练可使受调控基因总数增至近3000个，其中还包含诸多通常与神经可塑性无关的基因。尽管水迷宫训练本身即可调控近1800个基因，但当联合HDACi给药进行该认知训练时，所涉及的特异性mRNA、基因网络及生物学通路则与单独训练时存在显著差异。随后，我们进一步探究了HDACi治疗引发的突触蛋白应答是否同样依赖于近期认知活动，以及该可塑性在伴有记忆损伤的衰老大鼠体内是否发生改变。研究发现，当联合水迷宫训练与HDACi给药时，年轻大鼠海马体中的突触蛋白标记可出现选择性上调；而联合给药方案对衰老大鼠海马体的突触蛋白则无显著影响。本研究结果表明：当下进行的认知活动可强力调控HDACi治疗的分子效应，且近期认知活动与组蛋白乙酰化动态调控之间的相互作用，在衰老大鼠海马体中遭到了破坏。