Determining the role of mitochondrial trafficking in activity-dependent structural synaptic plasticity

项目总结/摘要 我们的大脑通过神经元之间错综复杂的电通信来执行复杂的认知任务。 这种交流发生的专门场所是突触，它能够进行各种形式的交流。 可塑性，使神经元之间的通信不断和自适应的完善。的 在突触处传递的神经元活动的量通常决定了修饰的类型，并且 提高神经元之间的交流水平，通过适应性的 连接数量的增加。这个过程统称为活动依赖性突触 可塑性，被认为是学习和记忆的细胞基础。 该项目的长期目标是更好地了解活动依赖性的基本细胞生物学根源 突触可塑性特别是，我有兴趣了解细胞内的功能作用， 线粒体运输支持适应增加的神经元活化的突触的生长。我会 我用果蝇幼虫或果蝇蛆作为实验模型来进行这个项目 系统被选中，因为强大的遗传工具可用。就像我们脊髓中的运动神经元一样， 幼虫体壁中的肌肉受运动神经元支配，运动神经元负责发送 移动时发出信号。这些运动神经元在肌肉上形成突触，这被称为 神经肌肉接头（NMJ）突触。NMJ突触的突触前末端会发生活动- 依赖可塑性的增加活动的运动神经元，从增加运动的幼虫。我可以 使用开发的技术直接通过幼虫的角质层（皮肤）对这种突触进行显微成像 在我的实验室里;包括它的形状变化和细胞内动力学（如线粒体的变化）， 当神经元活动增加时，与生长同时发生。 我的中心假设是，神经元活动诱导急性突触生长的形成， 最终通过线粒体的运输稳定到这个新生的增长，这有利于其长期 发育成成熟的突触连接。使用我描述的工具，我将检验这个假设 有两个具体的目的：（1）我将使用一个遗传突变的幼虫，其中线粒体贩运到NMJ 是功能失调，看看是否有任何方面的活动依赖性增长是成功的，因此，精确定位一个精确的 线粒体运输的作用。(2)我将试图从功能上描述一种分子介体 负责促进活动依赖性突触生长，并确定其驱动力是否 促进突触生长的能力在于其对线粒体运输的调节。从以下方面获得的见解 这项工作将揭示突触可塑性和线粒体运输的细胞生物学的新知识， 神经元，这两个过程通常会导致神经退行性疾病时，功能失调。

Project Summary/Abstract Our brains carry out complex cognitive tasks via the intricate electrical communication between neurons. The specialized site where this communication occurs is the synapse, and it is capable of various forms of plasticity that enable the constant and adaptive refinement of the communication between neurons. The amount of neuronal activity that is transmitted at the synapse typically dictates the type of modification, and raising the level of communication between neurons strengthens their synaptic connection through an adaptive increase in the number of connections. This process is collectively known as activity-dependent synaptic plasticity, and is thought to be the cellular foundation for learning and memory. The long term goal of this project is to better understand the basic cell biological roots of activity-dependent synaptic plasticity. In particular, I am interested in understanding the functional role of intracellular mitochondrial trafficking in supporting the growth of synapses adapting to increased neuronal activation. I will carry out this project using Drosophila Melanogaster larvae, or fruit fly maggots, as an experimental model system that was chosen due to the powerful genetic tools available. Like motor neurons in our spinal cord, the muscles in the body wall of the larvae are innervated by motoneurons that are responsible for sending the signal when to move. These motoneurons form a synapse onto the muscle, which is known as the neuromuscular junction (NMJ) synapse. The presynaptic terminal of the NMJ synapse will undergo activity- dependent plasticity upon increased activity of the motoneurons, from increased movement of the larvae. I can microscopically image this synapse directly through the cuticle (skin) of the larvae using technology developed in my lab; including its changing shape and intracellular dynamics (such as changes in mitochondria) that occur simultaneously with the growth when neuronal activity is increased. My central hypothesis is that neuronal activity induces the formation of acute synaptic growth that is eventually stabilized by the trafficking of mitochondria into this nascent growth, which facilitates its long-term maturation to becoming a mature synaptic connection. Using the tools I described, I will test this hypothesis with two specific aims: (1) I will use a genetic mutant larvae in which the trafficking of mitochondria to the NMJ is dysfunctional to see if any aspects of activity-dependent growth are successful, hence pinpointing a precise role for mitochondrial trafficking in the process. (2) I will seek to functionally characterize a molecular mediator responsible for promoting activity-dependent synaptic growth, and determine whether the driving force for its ability to promote the growth of synapses is in its regulation of mitochondrial trafficking. The insight gained from this work will uncover new knowledge on the cell biology of synaptic plasticity and mitochondrial trafficking in neurons, two processes that commonly result in neurodegenerative diseases when dysfunctional.