Project 5 Modulation and Function of 5HT2C Receptors

5-羟色胺受体的2C-亚型（5 HT 2CR）已经涉及许多人类精神和精神疾病。 行为障碍，包括MOD、心境恶劣、强迫症、焦虑和精神分裂症。 Emeson实验室的研究首次证明了5 HT 2CR的功能是 通过一种称为RNA编辑的新的RNA修饰过程来调节。5 HT 2CR转录本的编辑是 负责多达24种5 HT 2CR同种型的细胞特异性表达，并被提议用于 代表细胞通过改变细胞外信号来调节其应答的调节机制， 受体G蛋白相互作用的有效性和特异性。最近的研究表明， 诊断为精神疾病和抗抑郁药应答的患者中5 HT 2cR编辑的作用 和抗精神病药物治疗所提出的研究的长期目标是定义细胞 参与5 HT 2CR信号调节的机制，编辑的5 HT 2CR iso- 形式和5 HT 2cR编辑和情感障碍之间的可能关系。项目5：调制 和5-HT 2c受体的功能，罗恩埃米森提出了三个目标，以更全面地阐明该地区- 发育中的神经系统中5 HT 2cR编辑的特定模式，以检查遗传和表观遗传 调节5 HT 2CR编辑模式并利用独特的基因修饰小鼠品系 ly表达5 HT 2CR的单个编辑的同种型，以检查多种5 HT 2CR的生理相关性。 在Aim I中，Emeson将使用焦磷酸测序、引物延伸和基于qRT-PCR的strat- 因此，本研究旨在确定从脑缺血发作开始脑中表达的5 HT 2cR mRNA的区域特异性库。 成年期的5 HT 2CR表达，5 HT信号改变的小鼠品系中5 HT 2 pR编辑的变化- ing（例如SERT多态性，Pet-1敲除，重组近交系），以及定义 在基础状态下以及响应药理学和免疫学的下丘脑神经元中的5 HT 2CR编辑 生理紊乱在目标II中，Emeson建议进一步开发突变小鼠品系， 按下5 HT 2cR的未编辑（INI）或完全编辑（VGV）同种型，因为这些同种型显示 受体G蛋白偶联效率的最大差异。这些研究将检查和表征 “：5-HT 2CR mRNA和蛋白表达的模式和水平，并评估其分子基础 表达INI的小鼠中5 HT 2CR表达的减少可能代表了适应性稳态 机制这些研究将被扩展到研究突变小鼠信号的改变， GTPy 35 S结合和5 HT 2CR介导的反应性的变化，通过评估前阿片受体和受体的改变， omelanocortin表达和随后的进食行为。在目标III中，Emeson将检查表型 单一5 HT 2CR亚型的单独表达导致的后果，重点是观察到的缺陷， 表达INI的小鼠的母亲护理，以及中脑边缘多巴胺介导的奖励行为， 是这种行为改变的基础

The 2C-subtype of serotonin receptor (5HT2CR) has been implicated in a number of human psychiatric and behavioral disorders, including MOD, dysthymia, obsessive-compulsive disease, anxiety, and schizophrenia. Studies from the Emeson laboratory were the first to demonstrate that that the function of the 5HT2CR is modulated by a novel RNA modification process referred to as RNA editing. Editing of 5HT2CR transcripts is responsible for the cell-specific expression of as many as twenty-four 5HT2CR isoforms and is proposed to represent a regulatory mechanism by which cells modulate their response to extracellular signals by altering the efficacy and specificity of receptorG-protein interactions. More recent studies have demonstrated altera- tions in 5HT2cR editing in patients diagnosed with psychiatric disorders and in response to antidepressant and antipsychotic treatment. The long term objectives of the proposed research are to define the cellular mechanisms involved in the regulation of 5HT2CR signaling, the physiologic relevance of edited 5HT2CR iso- forms and possible relationships between 5HT2cR editing and affective disorders. In Project 5: Modulation and Function of 5-HT2c Receptors, Ron Emeson proposes three Aims to more fully elucidate the region- specific pattern of 5HT2cR editing in the developing nervous system, to examine genetic and epigenetic modulation of 5HT2CR editing patterns and to take advantage of genetically-modified mouse strains that sole- ly express a single, edited isoform of the 5HT2CR to examine the physiologic relevance of multiple 5HT2CR species in the CNS.In Aim I, Emeson will use pyrosequencing, primer-extension, and qRT-PCR-based strat- egies to define the region-specific repertoire of 5HT2cR mRNAs expressed in the brain from the onset of 5HT2CR expression through adulthood, changes in 5HT2pR editing in mouse strains with altered 5HT signal- ing (e.g.SERT polymorphisms, Pet-1knockout, recombinant inbred strains), as well as define the pattern of 5HT2CR editing in identified hypothalamic neurons in the basal state and in response to pharmacologic and physiologic perturbations. In Aim II, Emeson proposes to further develop mutant mouse strains solely ex- pressing the non-edited (INI) or fully-edited (VGV) isoforms of the 5HT2cR, since these isoforms demonstrate the greatest differences in receptorG-protein coupling efficacy. These studies will examine and characterize ":he pattern and level of expression of 5HT2CR mRNA and protein expression and assess the molecular basis of a decrease in 5HT2CR expression in INI-expressing mice that may represent an adaptive homeostatic mechanism. These studies will be extended to examine alterations in signaling for mutant mice using GTPy35S binding and changes in 5HT2CR-mediated responsiveness by assessing alterations in both pro-opi- omelanocortin expression and subsequent feeding behavior. In Aim III, Emeson will examine the phenotypic consequences resulting from sole expression of a single 5HT2CR isoform, focusing upon observed deficits in maternal care in INI-expressing mice, as well as mesolimbic dopamine-mediated reward behaviors that may underlie such behavioral alterations.