Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

动态平衡信号系统在突触处运行，以实现灵活而稳定的信息 在神经系统中转移。体内平衡信号的缺陷会导致癫痫发作， 兴奋性毒性、认知功能衰退和神经退化。尽管我们已经学到了很多 近年来关于突触用来中和扰动的表达机制 神经传递，快速启动并长期维持内环境平衡的途径 人们对信号仍然知之甚少。在这里，我们建议确定诱导机制 以果蝇神经肌肉接头为靶点调节动态平衡突触可塑性 独特而强大的模型体系。在这个谷氨酸能突触，药理学或遗传学 突触后神经递质受体的破坏触发逆行信号系统， 导致突触前谷氨酸释放的代偿性增加，以维持稳定的突触 强度，称为突触前内稳态增强(PHP)。这一过程与此类似 在各种其他生物体中观察到的现象，包括哺乳动物的中央突触。我们 最近发现了一种针对突触后底物的E3泛素连接酶适配器 隔室，并启用逆行内稳态信号。我们建议首先确定和 描述内稳态信号系统的突触后靶点。初步数据显示 突触后密度的一个关键组成部分对于逆行内稳态信号是必要的。 接下来，我们将定义介导PHP和PHP慢性表达的诱导机制 确定CaMKII在这一过程中的作用。最后，我们将审问药物学 PHP的诱导和验证跨突触复合体介导快速逆行的假说 动态平衡信号。这些研究将利用分子遗传、 电生理和创新的功能成像方法，共焦，超分辨率， 和超微结构水平来确定启动和维持 逆行动态平衡信号。总而言之，这些实验将增进我们对 赋予突触感知扰动的能力的基本机制 神经传递和适应性调节突触功能以稳定信息传递 神经系统。

Homeostatic signaling systems operate at synapses to enable flexible yet stable information transfer in the nervous system. Defects in homeostatic signaling contribute to seizures, excitotoxicity, cognitive decline, and neurodegeneration. Although much has been learned in recent years about the expression mechanisms synapses employ to counteract perturbations to neurotransmission, the pathways that rapidly initiate and chronically maintain homeostatic signaling remains poorly understood. Here, we propose to determine the induction mechanisms mediating homeostatic synaptic plasticity using the Drosophila neuromuscular junction as a unique and powerful model system. At this glutamatergic synapse, pharmacologic or genetic disruption to postsynaptic neurotransmitter receptors triggers a retrograde signaling system that leads to a compensatory increase in presynaptic glutamate release to maintain stable synaptic strength, referred to as presynaptic homeostatic potentiation (PHP). This process parallels similar phenomena observed in a variety of other organisms, including mammalian central synapses. We have recently discovered an E3 ubiquitin ligase adaptor that targets substrates in the postsynaptic compartment and enables retrograde homeostatic signaling. We propose to first identify and characterize postsynaptic targets of the homeostatic signaling system. Preliminary data suggests a key component of the postsynaptic density is necessary for retrograde homeostatic signaling. Next, we will define the induction mechanisms mediating the chronic expression of PHP and determine the role of CaMKII in this process. Finally, we will interrogate the pharmacological induction of PHP and test a hypothesis that trans-synaptic complexes mediate rapid retrograde homeostatic signaling. These studies will leverage a synergistic combination of molecular genetic, electrophysiological, and innovative functional imaging approaches at confocal, super resolution, and ultrastructural levels to determine the induction mechanisms that initiate and maintain retrograde homeostatic signaling. Together, these experiments will advance our understanding of the fundamental mechanisms that endow synapses with the capacity to sense perturbations to neurotransmission and adaptively modulate synaptic function to stabilize information transfer in the nervous system.