Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

 描述（由申请人提供）：从无脊椎动物到人类的神经系统已经显示出显著的弹性和适应能力，以保持稳定的功能，尽管存在可能导致次优或不受控制的活动的挑战。在这些系统中的每一个中，对突触活动的扰动最初导致突触神经元的相应改变。 实力然而，给予足够的时间，这些生物体中的神经系统通过调节突触前释放或突触后神经递质受体来适应，以重新靶向先前的突触强度水平。这个过程被称为稳态突触可塑性，被认为能够实现稳定但灵活的突触活动，并在调节健康和疾病的神经功能方面发挥关键作用。然而，在赋予突触这些非凡能力的分子和细胞机制方面，我们的知识存在重大空白。这个建议的长期目标是确定基因和阐明实现和维持突触强度的稳态控制的机制。为了了解稳态突触信号的原理，我们将利用果蝇神经肌肉接头，它已被建立为一个强大的遗传系统来研究这一过程。该建议将使用遗传分析，电生理学和成像方法相结合，以研究增强突触前释放的稳态机制，以响应突触后神经递质受体功能的扰动。特别是，已经确定了三个基因编码的神经元跨膜蛋白，似乎在突触前终端一起发挥作用，以促进钙依赖性，稳态增强突触传递。有趣的是，这些基因与癫痫、精神分裂症和双相情感障碍有关。拟议的实验将首先在突触功能和稳态可塑性方面表征这些分子。共聚焦和超分辨率显微镜将被用来揭示这些蛋白质的突触下定位和细胞活动。最后，提出了互补的正向遗传筛选，以确定新的基因，协调稳态突触可塑性。总之，这项工作有望揭示新的稳态基因和机制，控制突触强度的适应性调节，并提供一个基础，了解如何跨细胞稳态信号系统更普遍地建立在神经系统中。

 DESCRIPTION (provided by applicant): Nervous systems from invertebrates to humans have shown remarkably resilient and adaptive abilities to maintain stable functionality despite challenges that may otherwise lead to suboptimal or uncontrolled activity. In each of these systems, perturbations to synaptic activity initially lead to corresponding alterations in synaptic strength. However, given sufficient time, nervous systems in these organisms adapt by modulating presynaptic release or postsynaptic neurotransmitter receptors to re-target previous levels of synaptic strength. This process, termed homeostatic synaptic plasticity, is thought to enable stable, yet flexible, synaptic activity and to play key roles in tuning neural function in health and disease. Yet there is a major gap in our knowledge of the molecular and cellular mechanisms that endow synapses with these extraordinary abilities. The long term goal of this proposal is to identify the genes and elucidate the mechanisms that achieve and maintain the homeostatic control of synaptic strength. To understand the principles governing homeostatic synaptic signaling, we will utilize the Drosophila neuromuscular junction, which has been established as a powerful genetic system to study this process. This proposal will use a combination of genetic analysis, electrophysiology, and imaging approaches to investigate the homeostatic mechanisms that enhance presynaptic release in response to a perturbation to postsynaptic neurotransmitter receptor function. In particular, three genes encoding neuronal transmembrane proteins have been identified that appear to function together in the presynaptic terminal to promote the calcium-dependent, homeostatic potentiation of synaptic transmission. Interestingly, these genes have been associated with epilepsy, schizophrenia, and bipolar disorder. The proposed experiments will first characterize these molecules in synaptic function and homeostatic plasticity. Confocal and super-resolution microscopy will then be utilized to reveal the subsynaptic localization and cellular activities of these proteins. Finally, complementary forward genetic screens are proposed to identify new genes that orchestrate homeostatic synaptic plasticity. Together, this work is expected to reveal new homeostatic genes and mechanisms that control the adaptive modulation of synaptic strength and provide a foundation from which to understand how transcellular homeostatic signaling systems more generally are established in the nervous system.