Mechanism and Regulation of Serotonin Receptors in the Central Nervous System

描述(申请人提供)：5-羟色胺是大脑中一种普遍存在的神经递质，与各种精神障碍的病理生理学有关。因此，人们对了解5-羟色胺调节大脑中神经元功能的细胞和分子机制非常感兴趣。5-羟色胺通过7个不同的5-羟色胺受体家族在大脑中起作用。因此，了解不同5-羟色胺受体亚型的生理功能是试图了解5-羟色胺在大脑中如何发挥作用的重要一步。这个项目的长期目标是了解不同的5-羟色胺受体亚型的生理作用，以及这些影响的细胞和分子机制。在之前的资助期间，我们专注于几种不同类别的受体，包括5-HT1A、5-HT4和5-HT7受体。在目前的应用中，我们建议将这些研究扩展到5-HT2A亚型的受体。这些受体特别令人感兴趣，因为它们已被确定为经典致幻剂(如LSD)的靶标，并可能参与精神分裂症和抑郁症的病理生理学。在本项目中，我们建议结合电生理和分子生物学方法来了解5-HT2A受体如何调节大鼠前额叶皮质的神经元功能。在第一个特定的目标中，我们建议从机制上研究5-HT2A受体的激活如何增加该区域的谷氨酸突触传递。在第二个具体目标中，我们将测试5-羟色胺受体的一个重要作用是调节前额叶皮质突触可塑性的想法。最后，在第三个特定目标中，我们将测试支架蛋白，特别是MUPP1，在通过大脑中的5-HT2A受体组织信号方面发挥重要作用的假设。这三个特定目标结合在一起，将开始填补我们在理解5-HT2A受体在大脑皮层中的作用及其方式方面的一些空白。因此，这些研究应该有助于我们理解精神障碍的生物学基础。同样重要的是，我们希望这些研究也将有助于开发治疗这些疾病的新的治疗尿路方法。

DESCRIPTION (provided by applicant): Serotonin is a ubiquitous neurotransmitter in the brain that has been linked to the pathophysiology of avariety of mental disorders. As such, there is great interest in understanding the cellular and molecular mechanisms by which serotonin regulates neuronal functionin the brain. Serotonin acts in the brain through 7 different families of serotonin receptors. Therefore, understanding the physiological function of different serotonin receptor subtypes is an important step in trying to understand how serotonin works in the brain. The long term goal of this project is to understand the physiological role of different serotonin receptor subtypes, and the cellular and molecular mechanisms that underlie these effects. During previous funding periods we have focused on several distinct classes of receptors including 5-HT1A, 5-HT4 and 5-HT7 receptors. In the present application we propose to expand these studies to receptors of the 5-HT2A subtype. These receptors are particularly interesting because they have been identified as the targets for classic hallucinogens, such as LSD, and may participate in the pathophysiology of schizophrenia and depression, For the present project we propose to combine electrophysiological and molecular biological approaches to understand how 5-HT2A receptors regulate neuronal function in the rat prefrontal cortex. In a first Specific Aim we propose to examine mechanistically how activation of 5-HT2A receptors increase glutamate synaptic transmission in this region. In the second Specific Aim we will test the idea that one important effect of serotonin receptors is to regulate synaptic plasticity in prefrontal cortex. Finally, in a third Specific Aim, we will test the hypothesis that scaffolding proteins, and specifically MUPP1, play an important role in organizing signaling by 5-HT2A receptor in the brain.Combined, these three Specific Aims will begin to fill some of the gaps in our understanding of what 5-HT2A receptors do, and how they do it, in the cerebral cortex. As such, these studies should contribute to our understanding of the biological basis underlying mental disorders. Equally important, we hope these studies will also contribute to the development on novel therapeuric approaches for the treatment of these disorders.