Molecular mechanisms of STAT1 transcription factor in the pathogenesis of depression

血清中细胞因子浓度的升高通常在抑郁症患者中发现，而细胞因子如干扰素和白细胞介素早就被认为是通过转录因子STAT蛋白（信号转换器和转录激活因子）发出信号的。鉴于干扰素通过激活STAT1在细胞内对基因表达产生影响，本项目建议重点关注STAT1在抑郁样行为发病机制中的作用。目前，在现有文献中没有关于这一问题的可靠数据。因此，我们产生了一个具有缺陷的协同DNA结合的stat1敲入小鼠系，导致干扰素- γ介导的信号的全局丢失，并开始在行为测试中系统地评估该转基因小鼠系。这些实验的结果表明，纯合子敲入小鼠与表达野生型STAT1的同窝小鼠相比，在强迫游泳测试中表现出长时间的不动。初步实验显示STAT1和STAT3在海马神经元中均有表达。在这个项目中，我们计划研究这种干扰素- γ介导的信号转导的神经保护作用的潜在分子机制。将特别强调STAT1和STAT3异源二聚化对干扰素- γ介导的海马基因表达的重要性及其对抑郁样行为发展的可能影响。

Increased serum concentrations of cytokines are typically found in depressed patients, and cytokines such as interferons and interleukins have long been known to signal through transcription factors termed STAT proteins (signal transducer and activator of transcription). Given that interferons exert their intracellular effects on gene expression via activation of STAT1, this project proposal focuses on the role of STAT1 in the pathogenesis of depression-like behavior. Currently, there are no reliable data on this issue in the existing literature. Therefore, we generated a STAT1-knockin mouse line with defective cooperative DNA binding resulting in a global loss of interferon-gamma-mediated signaling and started to assess this transgenic mouse line systematically in behavioral tests. The results from these experiments demonstrated that homozygous knockin mice, when compared with their littermates expressing wild-type STAT1, exhibit a prolonged immobility in the forced-swim test. Preliminary experiments showed expression of both STAT1 and STAT3 in neurons of the hippocampal formation. In this project, we plan to study the underlying molecular mechanisms of this proposed neuroprotective effect of interferon-gamma-mediated signal transduction. Particular emphasis will be placed on the importance of heterodimerization of STAT1 and STAT3 for interferon-gamma-mediated hippocampal gene expression and its possible impact on the development of depression-like behavior.