Homeostatic Synaptic Depression

描述(申请人提供)：越来越多的证据表明，在从果蝇到老鼠和人类的各种生物中，神经功能通过稳态信号系统稳定下来。在每个例子中，在神经元或肌肉兴奋性的实验扰动之后，确定了稳态信号系统。在每个实验中，细胞通过调节离子通道丰度或突触传输来应对实验中的扰动，以抵消扰动并重新建立正常的活动水平。现在，人们普遍认为，体内平衡信号的缺陷会导致神经系统疾病的发生或发展。然而，动态平衡信号和疾病之间的明确联系将需要对潜在的信号系统有详细的细胞和分子理解。目前，内稳态信号的分子基础在很大程度上仍不清楚。在过去的十年里，我们已经建立了一个模型系统，用于快速鉴定和鉴定参与果蝇神经系统内稳态信号传递的基因。我们最近的成功之一是证明了人类精神分裂症相关基因dybindin对体内平衡信号至关重要。在初步数据中，我们鉴定了两种控制突触前神经末梢内稳态信号的新蛋白质，包括一种新的蛋白激酶和蛋白磷酸酶。我们建议对这些新基因进行表征，并定义它们如何在体内平衡信号中发挥作用。这两个基因在人类中都高度保守。

DESCRIPTION (provided by applicant): There is increasing evidence that neural function is stabilized by homeostatic signaling systems in organisms ranging from Drosophila to mouse and human. In each example, homeostatic signaling systems were identified following an experimental perturbation of neuronal or muscle excitability. In each experiment, the cells responded to the experimental perturbation by modulating ion channel abundance or synaptic transmission to counteract the perturbation and re-establish normal activity levels. It is now widely hypothesized that defective homeostatic signaling will contribute to the cause or progression of neurological disease. However, clear links between homeostatic signaling and disease will require a detailed cellular and molecular understanding of the underlying signaling systems. Currently, the molecular basis of homeostatic signaling remains largely unknown. Over the past ten years, we have established a model system for the rapid identification and characterization of genes involved in homeostatic signaling in the nervous system of Drosophila melanogaster. Among our recent successes has been the demonstration that a schizophrenia associated gene in human, dysbindin, is critical for homeostatic signaling. In preliminary data we identified two novel proteins that control homeostatic signaling within the presynaptic nerve terminal including a novel protein kinase and protein phosphatase. We propose to characterize these new genes and define how they function during homeostatic signaling. Both genes are highly conserved in human.