RNA editing in a transgenic mouse model of behavioral despair and anxiety.

描述（由申请人提供）：人类精神疾病的小鼠模型表明，慢性应激可导致抑郁症。缺乏5 HT 2CR的小鼠表现出应激反应、多动、食欲增加和肥胖的迹象。5 HT 2CR mRNA由两种酶ADAR 1和ADAR 2编辑，这两种酶属于称为作用于RNA的腺苷脱氨酶（阿达尔）的酶家族。ADAR 1和ADAR 2催化mRNA中腺苷转化为肌苷，因此具有改变氨基酸密码子的能力，这些氨基酸密码子可以产生许多蛋白质的同种型。ADAR 2能够自动编辑其自身的转录物，从而产生截短的蛋白质。为了测试自动编辑是否是一种调节机制，产生了过表达ADAR 2 cDNA的ADAR 2转基因小鼠。其结果是一种具有独特的表型改变的小鼠的发展。首先，转基因小鼠变得极度肥胖，这是成熟的开始。配对喂养研究显示，ADAR 2转基因小鼠表现出食物摄入增加，而没有任何明显的代谢失调。在肥胖之前，ADAR 2转基因小鼠具有正常的血浆葡萄糖、胰岛素和瘦素水平，但它们具有升高的皮质酮水平。最具挑衅性的是，当与年龄和体重匹配的对照同窝小鼠相比，ADAR 2转基因小鼠在Porsolt游泳和悬尾试验中的不动时间增加。Porsolt游泳和尾巴悬挂试验是可重复的和可预测的筛选抗抑郁药。这可能提示ADAR 2转基因小鼠是抑郁症相关行为的模型。有几条证据表明5 HT 2CR与精神疾病（包括抑郁症）有关。RNA编辑导致的5 HT 2CR的获得或丧失是产生精神病理学的潜在机制。ADAR 2 RNA编辑的后果之一是5 HT 2CR的改变。在本申请中待测试的假设是ADAR 2转基因小鼠已经改变了与抑郁症有关的脑亚区中的5 HT 2CR编辑，因此具有钝化的5-羟色胺突触功能，其诱导抑郁症样行为变化。ADAR 2转基因小鼠脑中抑郁相关行为和5 HT 2CR区域RNA编辑及其对特定抗抑郁药物的反应的进一步表征将提供一个机会，以评估潜在有价值的心理抑郁动物模型，并深入了解这种形式的情感障碍的机制。 公共卫生相关性：申请人最近开发了一种新的转基因小鼠品系，其可能与心理抑郁症的治疗具有直接的临床相关性。该应用程序的重点是验证ADAR 2转基因小鼠作为心理抑郁症的模型，以及5-羟色胺2C受体RNA编辑导致抑郁症的作用。该模型也可能是有用的，在检查神经基板或位点参与抑郁症。从啮齿动物模型预测心理抑郁症的临床结果可能进一步证明是有用的了解抗抑郁药的疗效和耐受性。

DESCRIPTION (provided by applicant): Mouse models of human psychiatric disorders show that chronic stress can lead to depression. Mice lacking 5HT2CR show signs of stress response, hyperactivity, increased appetite and obesity. 5HT2CR mRNA is edited by two enzymes ADAR1 and ADAR2 that belong to a family of enzymes known as adenonsine deaminases that act on RNA (ADAR). ADAR1 and ADAR2 catalyze the conversion of adenosine to inosine in mRNA and therefore have the ability to change amino acid codons that can produce numerous isoforms of proteins. ADAR2 is able to autoedit its own transcript resulting in a truncated protein. To test whether autoediting is a regulatory mechanism, ADAR2 transgenic mice were generated that over express ADAR2 cDNA. The result was the development of a mouse with unique set of phenotypic alterations. First the transgenic mice became extremely obese that was mature onset. Paired feeding studies showed ADAR2 transgenic mice exhibit increased food intake without any apparent metabolic dysregulation. Prior to obesity the ADAR2 transgenic mice have normal plasma glucose, insulin and leptin levels but they have elevated levels of corticosterone. Most provocative is that when compared with age and weight-matched control littermates, ADAR2 transgenic mice have increased immobility time in both the Porsolt swim and tail suspension test. The Porsolt swim and tail suspension tests are reproducible and predictable for screening antidepressants. This may suggest that ADAR2 transgenic mice are a model of depression related behaviors. Several lines of evidence have implicated 5HT2CR in psychiatric disorders including depression. A gain or loss of 5HT2CR as a result of RNA editing is a potential mechanism for generating psychopathology. One of the consequences of ADAR2 RNA editing is alterations in the 5HT2CR. The hypothesis to be tested in the present application is that ADAR2 transgenic mice have altered 5HT2CR editing in brain subregions that have been implicated in depression, and hence have a blunted serotonin synaptic function which induces depression-like behavioral changes. Further characterization of depression-related behaviors and regional RNA editing of 5HT2CR in the brain of ADAR2 transgenic mice and their response to specific antidepressant drugs will provide an opportunity to evaluate a potentially valuable animal model of psychological depression and to gain insight into the mechanisms of this form of affective disorder. PUBLIC HEALTH RELEVANCE: The applicant has recently developed a new line of transgenic mouse that may have direct clinical relevance for the treatment of psychological depression. This application focuses on validation of the ADAR2 transgenic mouse as a model of psychological depression and the role of serotonin 2C receptor RNA editing leading to depression. The model may also be useful in examining neuronal substrates or loci involved in depression. Predicting clinical outcomes from a rodent model of psychological depression may further prove to be useful for understanding the efficacy and tolerability of antidepressants.