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，慢性压力可导致抑郁症。缺乏5HT2CR的小鼠表现出应激反应、多动、食欲增加和肥胖的迹象。5HT2CR mRNA由两种酶ADAR1和ADAR2编辑，这两种酶属于作用于RNA的腺苷脱氨酶（ADAR）家族。ADAR1和ADAR2在mRNA中催化腺苷向肌苷的转化，因此能够改变氨基酸密码子，从而产生大量的蛋白质同工异构体。ADAR2能够自动编辑其自身的转录物，从而产生截断的蛋白质。为了验证自动编辑是否为一种调控机制，我们构建了ADAR2转基因小鼠，使其过表达ADAR2 cDNA。结果是培养出一组具有独特表型改变的小鼠。首先，转基因小鼠变得极度肥胖，这是成熟的开始。配对喂养研究表明，ADAR2转基因小鼠表现出食物摄入量增加，但没有任何明显的代谢失调。在肥胖之前，ADAR2转基因小鼠的血糖、胰岛素和瘦素水平正常，但皮质酮水平升高。最令人兴奋的是，与年龄和体重匹配的对照组相比，ADAR2转基因小鼠在Porsolt游泳和悬尾测试中都增加了静止时间。Porsolt游泳和悬尾试验是可重复和可预测的筛选抗抑郁药。这可能表明ADAR2转基因小鼠是抑郁症相关行为的模型。一些证据表明5HT2CR与包括抑郁症在内的精神疾病有关。由于RNA编辑导致的5HT2CR的增加或减少是产生精神病理的潜在机制。ADAR2 RNA编辑的后果之一是5HT2CR的改变。在目前的应用中需要验证的假设是，ADAR2转基因小鼠已经改变了与抑郁症有关的大脑亚区中的5HT2CR编辑，因此具有钝化的5 -羟色胺突触功能，从而诱导抑郁症样的行为改变。进一步表征ADAR2转基因小鼠的抑郁相关行为和大脑中5HT2CR的区域RNA编辑及其对特定抗抑郁药物的反应，将为评估心理抑郁的潜在有价值的动物模型提供机会，并深入了解这种形式的情感障碍的机制。

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.