Functions of D4 Dopamine Receptors in Prefrontal Cortex

描述（由申请人提供）：多巴胺D4受体在调节前额叶皮层（PFC）功能中起重要作用，前额叶皮层是一个与认知和情感过程密切相关的大脑区域。人类D4受体（hD 4 R）基因的一个独特特征是编码第三胞内环的外显子3存在大量多态性，该第三胞内环由可变数目（2-11）的串联重复序列组成。具有长重复序列的人类D4 R变体与注意力缺陷多动障碍（ADHD）和精神分裂症的执行控制过程的缺陷有关。本申请的目的是了解人类D4受体多态性的分子和生理基础。将使用组合方法来检验hD 4 R变体通过与不同蛋白质相互作用并激活不同的信号通路来差异地调节PFC神经递质传递和网络活动的假设，这有助于它们在心理健康中的不同作用 和失调使用体内病毒感染hD 4 R变体的D4 R敲除小鼠和人D4.7R（含有7个重复的ADHD连锁变体）敲入小鼠，我们将揭示不同的人D4 R变体对NMDAR运输和功能以及PFC锥体神经元中AMPAR介导的突触传递的影响。此外，我们还将评估人类D4 R变体对同步网络爆发的影响，这些网络爆发源于相互连接的神经元的大规模相关活动并控制选择性注意力。这项研究将大大推进我们对人类D4 R变异体的突触功能及其在精神障碍中的作用的理解。尖端技术的结合使用使我们能够有效地测试人类D4 R多态性在PFC电路中的功能作用。

DESCRIPTION (provided by applicant): The dopamine D4 receptor plays an important role in regulating functions of prefrontal cortex (PFC), a brain region critically involved in cognitive an emotional processes. A unique feature of human D4 receptor (hD4R) gene is the existence of a large number of polymorphisms in exon 3 that codes for the third intracellular loop, which consists of a variable number (2-11) of tandem repeats. Human D4R variants with long repeats have been associated with deficiencies in executive control processes in Attention Deficit and Hyperactivity Disorder (ADHD) and schizophrenia. The goal of this application is to understand the molecular and physiological basis of the polymorphism of human D4 receptors. Combined approaches will be used to test the hypothesis that hD4R variants regulate PFC glutamatergic transmission and network activity differentially by interacting with different proteins and activating distinct signaling pathways, which contributes to their different roles in mental health and disorders. Using D4R knockout mice with in vivo viral infection of hD4R variants and human D4.7R (ADHD-linked variant containing 7 repeats) knockin mice, we will reveal the impact of different human D4R variants on NMDAR trafficking and function and AMPAR-mediated synaptic transmission in PFC pyramidal neurons. Moreover, we will assess the effects of human D4R variants on synchronized network bursts, which originate from the large scale correlated activity of interconnected neurons and control selective attention. This study will significantly advance our understanding on the synaptic functions of human D4R variants and their role in mental disorders. The combined use of cutting-edge techniques enables us to effectively test the functional role of human D4R polymorphism in PFC circuits.