Homeostatic Synaptic Depression

描述（由申请人提供）：越来越多的证据表明，从果蝇到小鼠和人类，生物体内的神经功能是由稳态信号系统稳定的。在每个例子中，在神经元或肌肉兴奋性的实验扰动后，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递来抵消干扰并重新建立正常的活动水平，从而对实验扰动做出反应。现在广泛的假设是，有缺陷的稳态信号将有助于神经系统疾病的起因或进展。然而，要明确稳态信号和疾病之间的联系，需要对潜在的信号系统进行详细的细胞和分子理解。目前，稳态信号传导的分子基础仍是未知的。在过去的十年里，我们建立了一个快速识别和表征黑腹果蝇神经系统中参与稳态信号传导的基因的模型系统。我们最近的成功之一是证明了人类精神分裂症相关基因dysbindin对体内平衡信号至关重要。在初步数据中，我们确定了两种控制突触前神经末梢内稳态信号的新蛋白，包括一种新的蛋白激酶和蛋白磷酸酶。我们建议表征这些新基因，并确定它们如何在稳态信号传导过程中起作用。这两个基因在人类中都是高度保守的。

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.