School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
Neurobiol Learn Mem. 2012 May;97(4):425-40. doi: 10.1016/j.nlm.2012.03.007. Epub 2012 Mar 24.
Epigenetic mechanisms have recently been known to play fundamental roles in the regulation of synaptic plasticity, and learning and memory tasks in many brain regions, such as the hippocampus, the amygdala, the insular cortex. However, epigenetic mechanism in the medial prefrontal cortex (mPFC), also a crucial neural locus for the control of cognition and emotion, is not well known. The present study investigated the epigenetic regulation of two genes, reelin and brain-derived neurotrophic factor (bdnf), both play important roles in neural plasticity, in the mPFC. The data showed that the levels of total DNA methyltransferase (DNMTs), total histone acetyltransferases (HATs), global acetylated histone 3 (H3) and global acetylated histone 4 (H4) were all changed with the induction of long-term potentiation (LTP) in the mPFC, implying that DNA methylation and histone acetylation may involve in synaptic plasticity in the mPFC. The present results further demonstrated that the demethylation status of reelin and bdnf, and acetylated H3 and acetylated H4 at the reelin and the bdnf promoters in the mPFC were enhanced by the delivery of LTP-inducing high-frequency stimulation (HFS). Consistently, infusion of DNMT inhibitor, 5-azacytidine (5-azaC), or histone deacetylases (HDACs) inhibitor, sodium butyrate (NaB), into the mPFC could interfere with LTP-associated demethylation and acetylation of reelin and bdnf genes, and the induction of LTP as well. Long-term retention of trace fear memory, which is dependent on mPFC function, was also altered by administration of these inhibitors into the mPFC. These findings suggest that epigenetic regulation of DNA demethylation and histone acetylation of target genes, such as reelin and bdnf, might underlie the mechanisms of synaptic plasticity and memory retention in the mPFC.
表观遗传机制最近被发现，在调节包括海马体、杏仁核和岛叶皮层在内的许多脑区的突触可塑性、学习和记忆任务中起着至关重要的作用。然而，内侧前额叶皮层（mPFC）的表观遗传机制——该脑区对于控制认知和情绪也非常关键——却知之甚少。本研究探讨了两种基因（reelin 和 brain-derived neurotrophic factor，bdnf）的表观遗传调控，这两种基因在神经可塑性中都起着重要作用。数据显示，mPFC 中长时程增强（LTP）诱导后，总 DNA 甲基转移酶（DNMTs）、总组蛋白乙酰转移酶（HATs）、整体乙酰化组蛋白 3（H3）和整体乙酰化组蛋白 4（H4）的水平都发生了变化，这表明 DNA 甲基化和组蛋白乙酰化可能参与了 mPFC 中的突触可塑性。本研究结果进一步表明，mPFC 中 reelin 和 bdnf 的去甲基化状态，以及 reelin 和 bdnf 启动子上的 H3 和 H4 的乙酰化状态，均能因 LTP 诱导的高频刺激（HFS）的传递而增强。同样，将 DNA 甲基转移酶抑制剂 5-氮杂胞苷（5-azaC）或组蛋白去乙酰化酶（HDACs）抑制剂丁酸钠（NaB）注入 mPFC，可干扰 LTP 相关的 reelin 和 bdnf 基因去甲基化和乙酰化，以及 LTP 的诱导。记忆痕迹的长期保留依赖于 mPFC 的功能，而这些抑制剂注入 mPFC 也会改变这种记忆痕迹的长期保留。这些发现表明，靶基因如 reelin 和 bdnf 的 DNA 去甲基化和组蛋白乙酰化的表观遗传调控可能是 mPFC 中突触可塑性和记忆保留的机制之一。
