Mechanism and Regulation of 5HT Receptors in the CNS

描述（由申请人提供）：血清素是大脑中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，有很大的兴趣，了解细胞和分子机制，其中5-羟色胺调节神经功能的大脑。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工作的重要一步。 该项目的长期目标是了解不同5-羟色胺受体亚型的生理作用，以及这些作用背后的细胞和分子机制。在之前的资助期间，我们专注于几种不同类型的受体，包括5-HT 1A，5-HT 4和5-HT 7受体。在本申请中，我们建议将这些研究扩展到5-HT 2A亚型的受体。这些受体是特别有趣的，因为它们已被确定为经典的致幻剂，如LSD的目标，并可能参与精神分裂症和抑郁症的病理生理学，对于本项目，我们建议联合收割机电生理和分子生物学方法来了解5-HT 2A受体如何调节大鼠前额叶皮层的神经元功能。在第一个具体的目的，我们建议检查机械如何激活5-HT 2A受体增加谷氨酸突触传递在这一地区。在第二个具体目标中，我们将检验5-羟色胺受体的一个重要作用是调节前额叶皮层的突触可塑性。最后，在第三个特定目标中，我们将测试这样的假设：支架蛋白，特别是MPPP 1，在组织大脑中5-HT 2A受体的信号传导方面发挥着重要作用。结合起来，这三个特定目标将开始填补我们对5-HT 2A受体在大脑皮质中的作用以及如何发挥作用的理解中的一些空白。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新的治疗方法来治疗这些疾病。

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.