Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY 10605, USA.
Biochem Biophys Res Commun. 2010 Mar 19;393(4):673-7. doi: 10.1016/j.bbrc.2010.02.054. Epub 2010 Feb 17.
Most olfactory bulb (OB) interneurons are derived from neural stem cells in the subventricular zone (SVZ) and migrate to the OB via the rostral migratory stream (RMS). Mature dopaminergic interneurons in the OB glomerular layer are readily identified by their synaptic activity-dependent expression of tyrosine hydroxylase (TH). Paradoxically, TH is not expressed in neural progenitors migrating in the RMS, even though ambient GABA and glutamate depolarize these progenitors. In forebrain slice cultures prepared from transgenic mice containing a GFP reporter gene under the control of the Th 9kb upstream regulatory region, treatment with histone deacetylase (HDAC) inhibitors (either sodium butyrate, Trichostatin A or Scriptaid) induced Th-GFP expression specifically in the RMS independently of depolarizing conditions in the culture media. Th-GFP expression in the glomerular layer was also increased in slices treated with Trichostatin A, but this increased expression was dependent on depolarizing concentrations of KCl in the culture media. Th-GFP expression was also induced in the RMS in vivo by intra-peritoneal injections with either sodium butyrate or valproic acid. Quantitative RT-PCR analysis of neurosphere cultures confirmed that HDAC inhibitors de-repressed Th expression in SVZ-derived neural progenitors. Together, these findings suggest that HDAC function is critical for regulating Th expression levels in both neural progenitors and mature OB dopaminergic neurons. However, the differential responses to the combinatorial exposure of HDAC inhibitors and depolarizing culture conditions indicate that Th expression in mature OB neurons and neural progenitors in the RMS are regulated by distinct HDAC-mediated mechanisms.
大多数嗅球（OB）中间神经元来源于脑室下区（SVZ）的神经干细胞，并通过前迁移流（RMS）迁移到 OB。OB 肾小球层中的成熟多巴胺能中间神经元可通过其突触活性依赖性酪氨酸羟化酶（TH）表达来轻松识别。矛盾的是，尽管环境 GABA 和谷氨酸使这些祖细胞去极化，但 RMS 中迁移的神经祖细胞并不表达 TH。在含有 GFP 报告基因的转基因小鼠的前脑切片培养物中，该 GFP 报告基因受 Th 9kb 上游调控区的控制，用组蛋白去乙酰化酶（HDAC）抑制剂（丁酸钠、曲古抑菌素 A 或 Scriptaid）处理可特异性诱导 RMS 中的 Th-GFP 表达，而与培养基中的去极化条件无关。用 Trichostatin A 处理的切片中，肾小球层中的 Th-GFP 表达也增加，但这种表达增加依赖于培养基中去极化的 KCl 浓度。用丁酸钠或丙戊酸腹膜内注射也可在体内诱导 RMS 中的 Th-GFP 表达。神经球培养物的定量 RT-PCR 分析证实，HDAC 抑制剂可解除 SVZ 来源的神经祖细胞中 Th 表达的抑制。总之，这些发现表明，HDAC 功能对于调节神经祖细胞和成熟 OB 多巴胺能神经元中 Th 表达水平至关重要。然而，对 HDAC 抑制剂和去极化培养条件的组合暴露的不同反应表明，成熟 OB 神经元和 RMS 中的神经祖细胞中 Th 的表达受不同的 HDAC 介导的机制调节。
