Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia.
Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia.
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DOI：
10.1021/acschemneuro.6b00372
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发表时间：
2017-03-15
影响因子：
5
通讯作者：
Lipska BK
中科院分区：
文献类型：
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作者：
Schroeder FA;Gilbert TM;Feng N;Taillon BD;Volkow ND;Innis RB;Hooker JM;Lipska BK
死后脑研究支持组蛋白脱乙酰酶HDAC1和HDAC2的异常表达，这是包括精神分裂症、双相情感障碍和抑郁症在内的疾病的中心特征。我们的目标是研究HDAC在代表健康和疾病大脑的大尸检样本集中的表达。我们使用了来自确诊为精神分裂症(n=175)、严重抑郁障碍(n=135)和双相情感障碍(n=61)的患者的>；700个样本，通过实时定量聚合酶链式反应(RT-PCR)检测了与对照样本相比，背外侧前额叶皮质(DLPFC)和尾状核中HDAC1和HDAC2的转录水平。根据β-2-微球蛋白、β-葡萄糖苷酸酶和β-肌动蛋白的几何平均值计算HDAC的表达。在成年DLPFC中，精神分裂症样本中的HDAC2与对照组相比降低了34%(p<；10-4)。与对照组相比，重度抑郁症患者的HDAC2显著上调了17%(p=0.002)。吸烟史和治疗药物都不影响HDAC2水平，也没有观察到HDAC1患者对照的差异。在尾状核，患者组和对照组之间的HDAC水平没有变化。对照组DLPFC胎龄14~97岁(n=326)，HDAC1和HDAC2水平在出生前急剧下降，此后趋于稳定。使用迄今为止关于这一主题的最大尸检样本集，我们的主要发现(HDAC2转录本降低)在疾病(精神分裂症但不是严重抑郁障碍)、HDAC亚型(HDAC2但不是HDAC1)和大脑区域(DLPFC但不是尾状)显示出显著的特异性。这些差异塑造了对疾病大脑中神经回路的区域组件的理解，并建立了使用体内神经成像工具量化HDAC密度和分布的基准。
Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in diseases including schizophrenia, bipolar disorder, and depression. Our objective was to investigate HDAC expression in a large postmortem sample set representing healthy and disease brains. We used >700 well-characterized samples from patients diagnosed with schizophrenia (n = 175), major depressive disorder (n = 135), and bipolar disorder (n = 61) to measure HDAC1 and HDAC2 transcript levels by quantitative real-time PCR in dorsolateral prefrontal cortex (DLPFC) and caudate compared to control samples. HDAC expression was calculated relative to the geometric mean of β-2-microglobulin, β-glucuronidase, and β-actin. In adult-age DLPFC, HDAC2 was decreased by 34% in schizophrenia samples compared to controls (p < 10–4). HDAC2 was significantly upregulated in major depressive disorder samples by 17% versus controls (p = 0.002). Neither smoking history nor therapeutic drugs impacted HDAC2 levels and no HDAC1 patient-control differences were observed. In caudate, HDAC levels were unchanged between patient and control groups. In control DLPFC, age fetal week 14 to 97 years (n = 326), both HDAC1 and HDAC2 levels sharply declined around birth and stabilized thereafter. Using by far the largest postmortem sample set on this topic, our major finding (decreased HDAC2 transcript) showed notable specificity in disease (schizophrenia but not major depressive disorder), HDAC subtype (HDAC2 but not HDAC1) and brain region (DLPFC but not caudate). These differences shape understanding of regional components of neural circuitry in the diseased brain and set a benchmark to quantify HDAC density and distribution using in vivo neuroimaging tools.