Retraction or reshaping: dissecting the role of mitochondrial ROS in synaptic plasticity

项目摘要 神经元的功能需要通过一个 一个叫做突触可塑性的基本过程。众所周知， 神经传递是由突触前和突触后神经元之间的反馈信号调节的。 神经元，这导致短期和/或长期的结构适应。然而， 我们知道这个规则是如何产生的。目前的目标是阐明这一缺失 通过探索线粒体的新兴信号作用， 维持突触功能和可塑性的局部能量需求的细胞器。基于 神经元活动决定有氧能量转换的速度， 线粒体释放化学活性氧（ROS），我们假设 控制和定位线粒体释放ROS调节突触功能 和可塑性。我们的初步数据表明，线粒体ROS的释放可以是 在体内突触前末梢中特异性地引起。我们将率先使用 用于同步诱导和测量ROS排放的光遗传学 突触功能将使用超分辨率探索功能性ROS信号传导靶点 荧光显微镜和质谱法。重要的是，我们的合作者和我们 建立了一种方法，在短短几个小时内， 体内光遗传学我们的研究结果将影响旨在改善神经元功能的治疗方法。 与年龄相关的神经退行性变

PROJECT SUMMARY Neuronal function requires the reshaping and rewiring of neural connections through a fundamental process named synaptic plasticity. It is well known that the strength of neurotransmission is regulated by feedback signaling between the pre- and postsynaptic neuron, which leads to short- and/or long-term structural adaptations. However, little is known about how this regulation occurs. The current objective is to elucidate this missing mechanistic link by exploring emerging signaling roles of mitochondria, which are organelles that sustain the local energy demand of synaptic function and plasticity. Based on the rationale that neuronal activity sets the pace of aerobic energy conversion and of emission of chemically reactive oxygen species (ROS) from mitochondria, we hypothesize that controlled and localized mitochondrial emission of ROS regulates synaptic function and plasticity. Our preliminary data show that emission of mitochondrial ROS can be elicited specifically in presynaptic terminals in vivo. We will pioneer in the use of optogenetics for synchronized induction and measurement of ROS emission during synaptic function. Functional ROS signaling targets will be explored using super resolution fluorescence microscopy and mass spectrometry. Importantly, our collaborators and we established a method to elicit and study synaptic plasticity within just a few hours using optogenetics in vivo. Our results will impact therapies aimed improving neuronal communication in age-related neurodegeneration.