New transgenic mouse models to study the role of astrocytes in synaptogenesis in vivo

在大脑发育过程中，绝大多数突触连接是在星形胶质细胞（一种特定类型的神经胶质细胞）分化后形成的，并且在成人大脑中，大多数突触与星形胶质细胞过程密切接触。有越来越多的证据，主要来自体外研究，星形胶质细胞支持甚至主动控制突触连接的形成和功能，但由于缺乏合适的动物模型，这些相互作用在体内的相关性仍未得到证实。我们的项目旨在建立新的转基因小鼠模型，允许使用Cre-loxP技术在星形胶质细胞中进行时间控制的基因消除。这些转基因模型将首次允许测试星形胶质细胞在突触的形成、功能和可塑性中的作用以及在体内病理条件下的变性。具体来说，我们想测试我们目前的工作假设，出生后突触需要胆固醇，是由星形胶质细胞和脂蛋白提供。为了实现这一目标，我们将选择性地消除星形胶质细胞中的角鲨烯合酶，一种胆固醇生物合成的特异性酶，并研究对突触发生的影响。

During brain development, the large majority of synaptic connections is formed after the differentiation of astrocytes, a specific type of neuroglia, and in the adult brain most synapses are in close contact with astrocytic processes. There is increasing evidence, mainly from in vitro studies, that astrocytes support or even actively control the formation and function of synaptic connections, but the relevance of these interactions in vivo is still unproven due to a lack of suitable animal models. Our project aims to establish new transgenic mouse models, which allow for temporally controlled gene elimination in astrocytes using the Cre-loxP technique. These transgenic models will allow for the first time to test the role of astrocytes in the formation, function and plasticity of synapses as well as their degeneration under pathologic conditions in vivo. Specifically, we would like to test our current working hypothesis that postnatal synaptogenesis requires cholesterol that is produced by astrocytes and delivered via lipoproteins. To accomplish this, we will eliminate selectively in astrocytes the squalene synthase, a specific enzyme of cholesterol biosynthesis, and study the effects on synaptogenesis.