Department of Psychiatry, University of Illinois at Chicago, IL 60612, USA.
Biol Psychiatry. 2013 Apr 15;73(8):763-73. doi: 10.1016/j.biopsych.2013.01.012. Epub 2013 Feb 26.
Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown.
We measured amygdaloid HDAC activity, levels of HDAC isoforms, and histone H3 acetylation in selectively bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 small interfering RNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density.
We found that P rats innately display higher nuclear HDAC activity and HDAC2 but not HDAC 1, 3, 4, 5, and 6 protein levels and lower acetylation of H3-K9 but not H3-K14, in the CeA and medial nucleus of amygdala compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (Bdnf and Arc)-specific histone acetylation, and attenuated anxiety-like behaviors in P rats but had no effects in NP rats. The HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol but not sucrose consumption in P rats and increased histone acetylation of Bdnf and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density.
These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism.
表观遗传机制与包括酒精依赖在内的精神疾病有关。然而，特定组蛋白去乙酰化酶（HDAC）同工型在焦虑和酗酒的遗传易感性中的表观遗传基础和作用尚不清楚。
我们测量了选择性繁殖的酒精偏好（P）和非偏好（NP）大鼠杏仁核中的 HDAC 活性、HDAC 同工型水平和组蛋白 H3 乙酰化。我们采用 HDAC2 小干扰 RNA 输注到 P 大鼠的杏仁核中央核（CeA），以确定 HDAC2 在焦虑样和饮酒行为中的因果作用。进行染色质免疫沉淀分析，以检查脑源性神经营养因子（Bdnf）和活性调节细胞骨架相关蛋白（Arc）基因的组蛋白乙酰化状态。进行高尔基-考克斯染色以测量树突棘密度。
我们发现，与 NP 大鼠相比，P 大鼠天生在 CeA 和杏仁核内侧核中显示出更高的核 HDAC 活性和 HDAC2，但没有 HDAC1、3、4、5 和 6 蛋白水平，以及更低的 H3-K9 乙酰化，但 H3-K14 没有变化。急性乙醇暴露降低了杏仁核中的 HDAC 活性和 HDAC2 蛋白水平，增加了整体和基因（Bdnf 和 Arc）特异性组蛋白乙酰化，并减弱了 P 大鼠的焦虑样行为，但对 NP 大鼠没有影响。CeA 中的 HDAC2 敲低减弱了 P 大鼠的焦虑样行为和自愿饮酒但不是蔗糖消耗，并增加了 Bdnf 和 Arc 的组蛋白乙酰化，导致蛋白水平增加，与树突棘密度增加相关。
这些新数据表明，HDAC2 介导的表观遗传机制在焦虑和酗酒中起作用。
