Targeting astroglial metabolism in vivo: Consequences for astrocytes, neurons and synapses

不同类型脑细胞之间的代谢合作对于正常的大脑功能如突触传递和可塑性是必要的。NAD+ /NADH-氧化还原状态是细胞代谢的中心点，并且与神经元活性以及星形胶质细胞和神经元的代谢相互作用相耦合。它还调节基因表达，蛋白质功能和细胞的信号传导特性。然而，由于细胞类型的巨大复杂性和缺乏细胞类型特异性干预策略，很难理解细胞类型特异性代谢对原位和体内脑功能的贡献。在这个项目中，我们的目标是分析转移的星形胶质细胞NAD+ /NADH-氧化还原状态对星形胶质细胞和邻近神经元的基因表达，星形胶质细胞和突触信号传导和结构可塑性的影响。这将通过利用基于新策略的转基因小鼠模型来实现，该策略允许在体内以可诱导的并且重要的是细胞类型特异性的方式精确地转变NAD+ /NADH-氧化还原状态。这些实验将提供新的见解如何（星形胶质细胞）代谢有助于突触功能和可塑性，通过整合代谢状态，基因表达和信号。

Metabolic cooperation between different types of brain cells is necessary for proper brain function like synaptic transmission and plasticity. The NAD+ / NADH-redox state is a central point of cellular metabolism, and is coupled to neuronal activity as well as to the metabolic interaction of astrocytes and neurons. It also regulates gene expression, protein functions and signalling properties of cells. However, it has been difficult to appreciate cell type specific metabolic contributions to brain functions in situ and in vivo due to the enormous complexity of cell types and the lack of cell type specific intervening strategies. In this project, we aim to analyse the impact of a shifted astroglial NAD+ / NADH-redox state on astrocytes and neighbouring neurons regarding gene expression, astroglial and synaptic signalling, and structural plasticity. This will be achieved by taking advantage of a transgenic mouse model based on a new strategy, that allows to precisely shift the NAD+ / NADH-redox state in an inducible and, importantly, a cell type-specific manner in vivo. These experiments will provide novel insights how (astroglial) metabolism contributes to synaptic function and plasticity by integrating metabolic states, gene expression and signalling.