Role of the chemokine receptor CX3CR1 in neuronal transmission and brain development and its potential association with Attention Deficit/Hyperactivity Disorder (ADHD)

趋化因子CX3CL1 （fractalkine）除了在免疫系统中的功能外，还调节中枢神经系统（CNS）中的小胶质细胞激活、神经元发育和神经传递。CX3CL1粘附在神经元细胞膜上，在中枢神经系统中的表达水平高于外周。CX3CR1是相应的受体，主要在小胶质细胞上表达，调节神经元与小胶质细胞之间的通讯。行为测试表明，CX3CR1（-/-）小鼠对特定任务的专注能力受损，可能代表了注意力缺陷/多动障碍（ADHD）的一种新的动物模型。我们认为CX3CR1可能影响神经递质释放和参与注意力调节的大脑区域的发育。我们将通过磁共振成像研究CX3CR1（-/-）小鼠的脑容量和发育。通过CX3CR1（-/-）和野生型小鼠的脑切片和原代神经元培养，我们将研究电生理以及神经递质摄取和释放。此外，我们将通过免疫组织化学方法阐明小胶质细胞在CX3CR1(-/-)-和野生型小鼠脑发育中的作用。该项目的目标是表征一种新的ADHD动物模型，并为研究人类ADHD的发病机制开辟新的起点。

In addition to its functions in the immune system, the chemokine CX3CL1 (fractalkine) modulates microglia activation, neuronal development and neurotransmission in the central nervous system (CNS). CX3CL1 is tethered to the cell membrane of neurons and expressed in the CNS at higher levels than in the periphery. CX3CR1, the corresponding receptor, is mainly expressed on microglia cells, modulating neuron-microglia communication. Behavioral tests showed that CX3CR1(-/-) mice have impaired ability to focus on a specific task and may represent a new animal model for attention deficit/hyperactivity disorder (ADHD). We propose that CX3CR1 may influence neurotransmitter release and the development of brain areas involved in the regulation of attention. We will investigate brain volume and development in CX3CR1(-/-) mice by magnetic resonance imaging. With brain slices and primary neuron cultures from CX3CR1(-/-)- and wild-type mice we will study electrophysiology as well as neurotransmitter uptake and release. Moreover, we will elucidate the role of microglia in brain development by immunohistochemical methods in CX3CR1(-/-)- and wild-type mice. The goal of the project is to characterize a novel animal model for ADHD and to develop new starting points for the investigation of the pathogenesis of human ADHD.