Voltammetry of 5-HT Transmission in Psychiatric & Degenerative Disease Models

描述（由申请人提供）：已知5-羟色胺神经递质系统调节情绪、焦虑状态和认知。此外，改变的5-羟色胺传递被假设参与情绪和焦虑障碍以及包括阿尔茨海默病在内的神经退行性疾病的病因学和治疗。该项目旨在利用碳纤维微电极伏安法分析方法提供的高时间和空间分辨率来表征与精神病和退行性疾病直接相关的三种重要人类和小鼠模型中5-羟色胺神经传递的变化。拟议的研究将：（1）使用高速计时电流法评估人淋巴母细胞培养物中5-羟色胺再摄取动力学的差异，所述人淋巴母细胞培养物来源于具有由两个共同启动子多态性驱动的可变5-羟色胺转运蛋白表达的个体（5-HTTLPR和rs 25531）与罕见的常见强迫症形式中发现的Ile 425 Val编码区取代突变的组合;和（2）采用快速循环伏安法来表征5-羟色胺转运体敲除小鼠和脑源性神经营养因子（BDNF）敲除小鼠体内5-羟色胺释放和再摄取动力学的改变。我们的总体假设指出，潜在的微妙的，但生物学上重要的变化，多巴胺能神经传递发生在小鼠和人类的5-羟色胺转运蛋白表达改变。此外，我们的理论，在血清素传输的变化的基础上，年龄相关的退行性损失的神经支配的BDNF减少的小鼠。我们假设，快速电化学方法的应用是必要的，以检测这些变化的大脑神经传递，这是根本的调查的基本和疾病相关的过程。这些研究的结果将揭示伏安技术能够区分基因工程小鼠和人类细胞中改变的5-羟色胺神经传递的程度，这些细胞的遗传改变对于推进我们对精神病和神经退行性疾病的发病机制和治疗的认识很重要。

DESCRIPTION (provided by applicant): The serotonin neurotransmitter system is known to regulate emotion, anxiety states and cognition. Moreover, altered serotonin transmission is hypothesized to be involved in the etiology and treatment of mood and anxiety disorders, and neurodegenerative diseases including Alzheimer's disease. This project is designed to take advantage of the high temporal and spatial resolution afforded by carbon fiber microelectrode voltammetry analytical methods to characterize changes in serotonin neurotransmission in three important human and mouse models with direct relevance to psychiatric and degenerative disorders. The proposed research will: (1) Use high-speed chronoamperometry to evaluate differences in the kinetics of serotonin reuptake in human lymphoblast cell cultures derived from individuals with variable serotonin transporter expression driven by two common promoter polymorphisms (5-HTTLPR and rs25531) in combination with an lle425Val coding region substitution mutation found in rare familiar forms of obsessive compulsive disorder; and (2) Employ fast cyclic voltammetry to characterize alterations in the dynamics of serotonin release and reuptake in vivo in serotonin transporter knockout mice and brain-derived neurotrophic factor (BDNF) knockout mice. Our overarching hypothesis states that potentially subtle but biologically important changes in serotonergic neurotransmission occur in mice and humans with altered serotonin transporter expression. Further, we theorize that changes in serotonin transmission underlie age-related degenerative loss of serotonergic innervation in mice with reduced BDNF. We postulate that application of fast electrochemical methods is necessary to detect these changes in brain neurotransmission, which are fundamental to the investigation of basic and disease-related processes. This outcome of these studies will reveal the extent to which voltammetric techniques are able to differentiate altered serotonin neurotransmission in genetically engineered mice and human cells with genetic alterations important for advancing our knowledge of the pathogenesis and treatment of psychiatric and neurodegenerative diseases.