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

柯萨奇病毒和腺病毒受体 CAR 在突触传递和记忆形成中的作用

• 批准号: 313912461
• 负责人: Professor Dr. Michael Gotthardt
• 金额: --
• 依托单位: Forschungsgruppe Neuromuskuläre und kardiovaskuläre Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/313912461?language=en
• 关键词: Role; Coxsackievirus; Adenovirus; Receptor; CAR

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.

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、胰腺炎和脑膜脑炎相关的病毒受体。CAR主要在发育中的心脏和大脑中表达，出生后下调，并在疾病中重新诱导。它的功能主要在心脏中进行分析，它有助于胚胎和成人重塑。此外，我们最近发现了CAR在从心房到心室的电传导中的新作用，其涉及CAR与间隙连接蛋白的相互作用，并提出了CAR在突触传递中的类似作用。为了验证这一假设，我们已经产生了脑特异性CAR敲除小鼠，并发现在这些动物中促进了神经元之间的通信。我们的初步分析表明CAR KO小鼠中突触信号传递和长时程增强得到改善。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如何影响空间和情境学习，其在突触囊泡的胞吞和胞吞中的作用，以及其对突触前和突触后蛋白的定位和功能的影响。因此，拟议的分子和功能分析可以将CAR确定为改善衰老和疾病中记忆形成的治疗靶点。

项目成果

The cell adhesion protein CAR is a negative regulator of synaptic transmission

细胞粘附蛋白 CAR 是突触传递的负调节因子

• DOI: 10.1038/s41598-019-43150-5
• 发表时间: 2019
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Wrackmeyer;Kaldrack;Jüttner;Pannasch;Gimber;Freiberg;Schmitz;Haucke;Rathjen;Gotthardt
• 通讯作者: Gotthardt