Mechanisms and Regulation of 5-HT Receptors in the CNS

描述(申请人提供)：神经递质5-羟色胺被认为在中枢神经系统具有广泛的功能，有助于行为和认知的生物学基础。这种神经递质也与精神障碍有关，特别是焦虑和抑郁，几种用于治疗这些疾病的药物针对大脑中的5-羟色胺能系统。5-羟色胺通过多个5-羟色胺受体来调节神经元活动，在过去的十年中，我们在理解这些受体的基本生物学方面取得了非凡的进展。然而，我们对这些受体如何在神经元中发挥作用，它们发出什么信号，以及它们如何在中枢神经系统中发出信号的了解仍然很少。这是一个重要的漏洞，因为精神障碍的生物学基础以及更好的治疗方法的开发将植根于这些受体使用的特定机制。PI的研究计划的长期目标是帮助在分子水平上对中枢神经系统神经元中5-羟色胺受体功能的机械性理解。具体地说，在这一应用中，我们建议使用电生理和分子生物学方法的协同组合来了解大脑皮层中5-HT2A受体使用的信号机制。该申请提出了三个具体目标。第一部分将阐明5-HT2A受体调节前额叶皮质锥体细胞膜兴奋性的近端信号机制。第二个目标将验证5-HT2A受体通过降低细胞膜PtdIns(4，5)2的浓度来抑制锥体细胞中存在的缓慢的钙激活钾电流的想法。第三个特定目标将确定5-HT2A受体如何去极化和兴奋锥体细胞。这个项目的结果应该有助于我们理解大脑中的5-羟色胺能机制，并因此有助于我们理解精神障碍，同时支持寻找更有效的治疗方法。公共卫生相关性：神经递质5-羟色胺与焦虑和抑郁的发生以及几种有效治疗精神障碍的药物的作用机制有关。这项申请中提出的研究旨在阐明5-羟色胺用来调节脑细胞和大脑回路功能的分子机制。这个项目的结果应该有助于我们更好地了解精神障碍，并为寻找更有效的治疗方法做出贡献。

DESCRIPTION (provided by applicant): The neurotransmitter serotonin is thought to have broad functions in the central nervous system, contributing to the biological basis underlying both behavior and cognition. This neurotransmitter has also been implicated in mental disorders, especially anxiety and depression, and several pharmacological agents used to treat these diseases target serotonergic systems in the brain. Serotonin acts through multiple serotonin receptors to regulate neuronal activity and work during the last decade has made extraordinary advances in our understanding of the basic biology of these receptors. However our understanding of how these receptors function within neurons, what they signal and how they signal in the central nervous system, is still poorly understood. This is an important lacunae, since the biological basis of mental disorders, as well as the development of better treatments, will be grounded in the specific mechanisms used by these receptors. The long term goal of the PI's research program is to help develop a mechanistic understanding, at the molecular level, of serotonin receptor function in central nervous system neurons. Specifically in this application we propose to use a synergistic combination of electrophysiological and molecular biological approaches to understand the signaling mechanisms used by 5-HT2A receptors in the cerebral cortex. The application proposes three Specific Aims. The first of these will elucidate the proximal signaling mechanism used by 5-HT2A receptors to regulate membrane excitability in pyramidal cells of the prefrontal cortex. The second Aim will test the idea that 5-HT2A receptors inhibit the slow calcium-activated potassium current present in pyramidal cells by reducing the concentration of membrane PtdIns(4,5)2. The third Specific Aim will determine how 5-HT2A receptors depolarize and excite pyramidal cells. The results of this project should contribute to our understanding of serotonergic mechanisms in the brain and, as such, contribute to our understanding of mental disorders while supporting the search for more effective treatments. The Public Health Relevance: The neurotransmitter serotonin has been implicated in the genesis of anxiety and depression and in the mechanism of action of several drugs effective in the treatment of mental disorders. The research proposed in this application seeks to elucidate the molecular mechanisms used by serotonin to regulate the function of brain cells and brain circuits. The results of this project should help us better understand mental disorders and contribute to the search of more effective treatments.