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质（PFC）的功能中起重要作用，前额叶皮质是一个关键的大脑区域，参与认知和情绪过程。人类D4受体（hD4R）基因的一个独特特征是在编码第三胞内环的外显子3上存在大量多态性，该环由可变数量（2-11）串联重复序列组成。具有长重复的人类D4R变异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。本应用程序的目的是了解人类D4受体多态性的分子和生理基础。将采用综合方法来验证hD4R变体通过与不同蛋白质相互作用和激活不同信号通路来调节PFC谷氨酸能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

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.