Consequences of HDAC2 inhibition in VTA-NAc circuitry

摘要 双相情感障碍是一种常见的精神疾病，治疗选择很少，也无法治愈。其中最 治疗急性躁狂症和稳定情绪的常用药物是抗惊厥药 丙戊酸盐药物(VPA；商品名Depakote)。这种药从20世纪90年代中期就开始使用了，但不是 在治疗效果方面，每个人对VPA的反应都是一样的，它可以产生多种，通常是严重的副作用 效果。此外，VPA有多种分子靶点，目前尚不清楚哪些靶点具有治疗作用。 切合实际。更好地了解VPA导致躁狂正常化的分子机制可能会 导致在未来更有针对性的治疗，产生更高的治疗反应和更少的副作用。 在这笔赠款的第一个资金周期中，我们发现VPA的治疗作用似乎是通过它的 抑制一种称为组蛋白脱乙酰基酶2(HDAC2)的蛋白质，这种蛋白质特异性地存在于大脑中包含 腹侧被盖区(VTA)内有大量多巴胺能神经元。HDAC2参与了该调控 因此，虽然抑制这种蛋白的作用可能比VPA更有针对性 治疗，它仍然有利于我们找出重要的基因，谁的表达发生了变化 VTA中HDAC2的抑制作用。为了识别这些靶点，我们将首先确定哪些基因通常是结合的 通过HDAC2，以及组蛋白乙酰化发生了什么变化，以响应HDAC2抑制在VTA使用 动物模型的行为特征与人类躁狂惊人地相似，并增加了多巴胺能 VTA内的活动。然后我们将确定HDAC2发生了哪些基因和蛋白质表达的变化 并将这些结果与第一个目标的结果以及我们先前的结果相结合，以确定特定的 可能是治疗候选的蛋白质。在目标3中，我们将确定HDAC2的影响 HDAC2对小鼠VTA多巴胺能活动和信号转导的抑制和靶向基因 帮助确定HDAC2目标基因可能使人类躁狂正常化的机制。总而言之，这是 研究将帮助我们确定治疗双相情感障碍的新治疗靶点及其作用机制 无序。

ABSTRACT Bipolar disorder is a common psychiatric disease with few treatment options and no cure. One of the most commonly prescribed medications for treatment of acute mania and mood stabilization is the anticonvulsant drug, valproate (VPA; trade name Depakote). This medication has been used since the mid-1990s, however not everyone responds equally to VPA in terms of therapeutic efficacy and it can produce multiple, often severe side effects. Moreover, VPA has a variety of molecular targets and it is unclear which targets are therapeutically relevant. Better understanding of the molecular mechanisms that normalize mania in response to VPA could lead to more targeted treatments in the future which produce a higher therapeutic response with less side effects. In the first funding cycle of this grant, we discovered that the therapeutic actions of VPA appear to occur via it’s inhibition of a protein called histone deacetylase 2 (HDAC2) specifically in a part of the brain that contains a large number of dopaminergic neurons, the ventral tegmental area (VTA). HDAC2 is involved in the regulation of gene expression on a wide scale, so while the inhibition of this protein is perhaps more targeted than VPA treatment, it is still advantageous for us to identify the important genes who’s expression is changed as a result of HDAC2 inhibition in the VTA. To identify these targets, we will first determine which genes are normally bound by HDAC2 and what changes to histone acetylation occur in response to HDAC2 inhibition in the VTA using two animal models that have a behavioral profile that is strikingly similar to human mania and increased dopaminergic activity in the VTA. We will then determine which gene and protein expression changes occur with HDAC2 inhibition and combine these results with those of the first Aim, and our prior results, to determine the particular proteins that might be likely therapeutic candidates. In Aim 3 we will then determine the impact of HDAC2 inhibition and direct target genes of HDAC2 on VTA dopaminergic activity and signaling in our mouse models to help identify the mechanisms by which HDAC2 target genes might normalize human mania. Taken together, this study will help us to identify novel therapeutic targets and their mechanism of action for the treatment of bipolar disorder.