Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

 描述(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，尽管挑战可能导致次优或不受控制的活动。在这些系统中，对突触活动的扰动最初会导致突触的相应变化 力量。然而，如果有足够的时间，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，以重新定位之前的突触强度水平。这一过程被称为稳态突触可塑性，被认为能够实现稳定而灵活的突触活动，并在调节健康和疾病的神经功能方面发挥关键作用。然而，我们对赋予突触这些非凡能力的分子和细胞机制的了解存在很大差距。这一建议的长期目标是识别基因，并阐明实现和维持对突触强度的动态平衡控制的机制。为了了解动态平衡突触信号传递的原理，我们将利用果蝇神经肌肉接头来研究这一过程，果蝇神经肌肉接头已被建立为一个强大的遗传系统。这项建议将结合遗传分析、电生理学和成像方法来研究在突触后神经递质受体功能的扰动下促进突触前释放的动态平衡机制。特别是，三个编码神经元跨膜蛋白的基因已经被发现，它们似乎在突触前末端共同发挥作用，促进突触传递的钙依赖、内稳态增强。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。拟议的实验将首先描述这些分子在突触功能和稳态可塑性方面的特征。然后将利用共聚焦显微镜和超分辨率显微镜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，以确定协调内稳态突触可塑性的新基因。总之，这项工作有望揭示控制突触强度的适应性调节的新的动态平衡基因和机制，并提供一个基础，以了解跨细胞动态平衡信号系统是如何在神经系统中建立的。

 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.