Role of the Coxsackievirus and Adenovirus Receptor CAR in Synaptic Transmission and Memory Formation

柯萨奇病毒-腺病毒-受体(CAR)是免疫球蛋白超家族(IgSF)的一种跨膜蛋白，最初被鉴定为与人类心肌炎、胰腺炎和脑膜炎相关的病毒受体。CAR主要在发育中的心脏和大脑中表达，出生后表达下调，在疾病中重新诱导。它的功能主要是在心脏中分析的，在那里它有助于胚胎和成人的重塑。此外，我们最近发现了CAR在从心房到心室的电传导中的一个新的作用，该作用与CAR与缝隙连接蛋白的相互作用有关，并提出了CAR在突触传递中的类似作用。为了验证这一假设，我们产生了大脑特异的汽车基因敲除小鼠，并发现这些动物之间的神经元之间的交流是容易的。我们的初步分析表明，CAR KO小鼠的突触信号传递和长时程增强有所改善。我们将在分子、细胞和器官水平上研究这些表型，以阐明CAR在神经元传递中的作用。因此，我们计划分析CAR如何影响空间和语境学习，它在突触小泡内外吞作用中的作用，以及它对突触前和突触后蛋白定位和功能的影响。大脑中特定的CAR基因敲除呈现出突触传递的改善，这应该转化为认知功能的增强。因此，拟议的分子和功能分析可以建立CAR作为治疗目标，以改善衰老和疾病中的记忆形成。

The Coxsackievirus-adenovirus-receptor (CAR) is a transmembrane protein of the Immunoglobulin-superfamily (IgSF) and was initially identified as a virus receptor related to human myocarditis, pancreatitis and meningoencephalitis. CAR is predominantly expressed in the developing heart and brain, downregulated after birth, and re-induced in disease. Its function was primarily analyzed in the heart where it contributes to embryonic and adult remodeling. In addition, we have recently uncovered a novel role for CAR in electrical conduction from atrium to cardiac ventricle that relates to the interaction of CAR with gap-junction proteins and proposed a similar role of CAR in synaptic transmission. To test this hypothesis, we have generated brain specific CAR knockout mice and found that communication between neurons is facilitated in these animals. Our preliminary analysis suggests improved synaptic signal transmission and long-term potentiation in CAR KO mice. We will study these phenotypes on the molecular, cellular, and organ level to elucidate the role of CAR in neuronal transmission. Accordingly, we plan to analyze how car affects spatial and contextual learning, its role in exo- and endocytosis of synaptic vesicles, and its effect on localization and function of pre- and post-synaptic proteins.The brain specific CAR knockout presents with improved synaptic transmission, which should translate to enhanced cognitive function. Thus, the proposed molecular and functional analysis could establish CAR as a therapeutic target to improve memory formation in ageing and disease.