Functions of D4 Dopamine Receptors in Prefrontal Cortex

描述(申请人提供)：多巴胺D4受体在调节前额叶皮质(PFC)的功能中起着重要作用，PFC是大脑中关键的认知和情绪过程区域。人类D4受体(HD4R)基因的一个独特特征是编码第三细胞内环的外显子3存在大量的多态性，该环由数量可变的(2-11)个串联重复组成。人类长重复的D4R变体与注意力缺陷和多动障碍(ADHD)和精神分裂症的执行控制过程缺陷有关。这项应用的目的是了解人类D4受体基因多态性的分子和生理基础。我们将使用组合的方法来检验这一假设，即hD4R变体通过与不同的蛋白质相互作用并激活不同的信号通路来不同地调节PFC谷氨酸能传递和网络活动，这有助于它们在精神健康中扮演不同的角色。 和精神障碍。利用体内感染hD4R变异体的D4R基因敲除小鼠和人D4.7R(包含7个重复的ADHD连锁变异体)敲打小鼠，我们将揭示不同的人D4R变异体对PFC锥体神经元NMDAR运输和功能以及AMPAR介导的突触传递的影响。此外，我们将评估人类D4R变体对同步网络突发的影响，同步网络突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。这项研究将极大地促进我们对人类D4R突触功能及其在精神障碍中的作用的理解。结合使用尖端技术，我们能够有效地测试人类D4R基因多态性在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.