D3 pre-mRNA processing in chronic psychosis

描述(由申请人提供)： 在慢性精神病患者的大脑中，一种异常升高的 多巴胺D3受体编码的前体mRNA的选择性剪接导致 D3受体mRNA表达显著降低，AN表达增加 选择性剪接、截短的类似D3的mRNA的积累，命名为D3nf D3nf mRNA被翻译成一种参与异寡聚体的蛋白质 具有全长D3受体蛋白的组件。与单体和 同源低聚D3蛋白，D3ID30f杂低聚体不与配体结合 亲和力强。因此，D3-Pre-mRNA的增强选择性剪接和 D3/D3nf蛋白的异寡聚体组装导致其表达降低 功能性D3受体。这一竞争续签旨在延长我们之前的 大脑皮层D3和D3nf基因相对表达的死后研究 新的精神分裂症患者及其配对人群的地区 控制。进一步的研究使用体内RNA剪接分析结合 底物D3前信使核糖核酸检测磷脂酶C活性在 D3和D3nf特异性剪接位点选择的调控。其他研究 使用基因敲除小鼠来研究D3受体失活的功能后果。 我们的研究表明，D3受体失活会导致 至少两个调节神经元活动的基因(c-fos， Calbindin)在解剖结构中与这些认知密切相关 精神分裂症患者易受干扰的过程。因此，一个系列 解剖学和生物化学研究的目的是阐明导致 D_1受体介导的小鼠新皮质c-fos反应减弱 D3和D2受体。对这些突变体的更多行为研究进一步 测试这种D1受体活性的下降是否会对他们的 认知任务中的表现。免疫细胞化学的最后一系列 实验检测纹状体钙结合蛋白的表达 由于D3受体的表达，D3突变体中钙结合蛋白的表达减少 促进共表达D3的腹侧纹状体神经元中钙结合蛋白的表达 受体和钙结合蛋白，或者是因为D3-受体在 纹状体钙结合蛋白表达系统的出生后发育。

DESCRIPTION (provided by applicant): In brains of patients with chronic psychosis, an abnormally increased alternative splicing of dopamine D3 receptor-encoded pre-mRNA leads to a significant decrease in the expression of D3 receptor mRNA and an increased accumulation of the alternatively-spliced, truncated D3-like mRNA, named D3nf D3nf mRNA is translated into a protein that participates in heteroligomeric assemblies with full-length D3-receptor protein. In contrast to monomeric and homoligomeric D3 proteins, the D3ID30f heteroligomers do not bind ligands with high affinity. Thus, both enhanced alternative splicing of D3-pre-mRNA and the heteroligomeric assembly of D3/D3nf proteins lead to a decreased expression of functional D3 receptors. This competing renewal seeks to extend our previous postmortem study on the relative expression of D3 and D3nf mRNAs in cortical regions of a new population of schizophrenic patients and their matched controls. Further studies use in vivo RNA splicing assays in conjunction with substrate D3 pre-mRNA to test the role of phospholipase C activity in the regulation of D3- and D3nf-specific splice-site selections. Additional studies use knockout mice to study functional consequences of D3 receptor inactivation. Our studies have shown that D3 receptor inactivation leads to a decreased expression of at least two genes that modulate neuronal activity (c-fos, calbindin) in anatomic structures critically involved in those cognitive processes that are vulnerable to disruption in schizophrenia. Thus, one series of anatomic and biochemical studies aims at elucidating mechanisms that lead to a decreased D1-receptor-mediated neocortical c-fos response in mice deficient for D3 and D2 receptors. Additional behavioral studies on these mutants further test whether this decreased D1-receptor activity has consequences for their performance in cognitive tasks. A final series of immunocytochemical experiments tests whether the expression of the striatal calcium-binding protein calbindin is decreased in D3 mutants because D3 receptor expression promotes calbindin expression in ventral striatal neurons that co-express D3 receptors and calbindin or because D3-receptors play a more general role in the postnatal development of the striatal calbindin-expressing system.