Homeostatic Stabilization of Neural Function in Health and Disease

项目总结/摘要 大脑的复杂性和变化能力令人惊讶。似乎可以肯定的是， 我们的学习和记忆能力只有在稳定、可复制、 可预测的基线神经功能。现在很清楚的是，稳态信号系统的功能贯穿于整个细胞。 中枢和外周神经系统，以稳定整个生命的神经功能。因此， 人们普遍认为，受损或适应不良的稳态信号传导将与病因直接相关， 神经系统疾病的进展，包括癫痫，自闭症和神经变性。但尽管 广泛的证据表明，在整个动物王国中， 与疾病和衰老的相关性，对潜在的机制知之甚少。体内平衡领域 可塑性是开放的探索和潜力的变革性进展，在细胞和 分子神经科学是巨大的。我们正在引领内稳态可塑性这一新兴领域， 利用无偏见的模型系统遗传学的力量来识别和表征从根本上新的 神经系统内稳态信号传导的细胞和分子机制。我们的实验将 定义了许多被鉴定为参与稳态信号传导系统的第一信号传导途径， 控制突触前神经递质释放和内在神经兴奋性。我们的方法发现了一个 先天免疫信号系统的新活性，新的跨突触信号通路，新的钙离子通道， 传感器，新的神经元激酶信号系统，突触前内质网的新作用， 与神经系统疾病的联系因此，我们的数据将为探索 哺乳动物神经疾病模型中的稳态可塑性，包括癫痫、自闭症和 神经变性我们的数据也将直接影响目前的理论和模型的稳态信号。 目前的理论模型已经引起了广泛的兴趣。分子洞察力将提供重要的新的 思想和新的约束下一代的理论模型的稳态可塑性，学习和 记忆

PROJECT SUMMARY/ABSTRACT The brain is astonishing in its complexity and capacity for change. It seems certain that the plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. It is now clear that homeostatic signaling systems function throughout the central and peripheral nervous systems to stabilize neural function throughout life. As a consequence, it is widely believed that impaired or maladaptive homeostatic signaling will be directly relevant to the cause and progression of neurological diseases that include epilepsy, autism and neurodegeneration. However, despite widespread evidence for the homeostatic control of neural function throughout the animal kingdom and implicit relevance to disease and aging, very little is known about the underlying mechanisms. The field of homeostatic plasticity is wide open for exploration and the potential for transformative advancement in cellular and molecular neuroscience is tremendous. We are leading the rapidly emerging field of homeostatic plasticity, harnessing the power of unbiased model system genetics to identify and characterize fundamentally new cellular and molecular mechanisms of homeostatic signaling in the nervous system. Our experiments will define many of the first signaling pathways identified to participate in the homeostatic signaling systems that control presynaptic neurotransmitter release and intrinsic neural excitability. Our approaches have uncovered a novel activity of the innate immune signaling system, new trans-synaptic signaling pathways, novel calcium sensors, novel neuronal kinase signaling systems, new roles for the presynaptic endoplasmic reticulum and tangible links to neurological disease. As such, our data will provide a foundation for exploring the impact homeostatic plasticity in mammalian models of neurological disease including epilepsy, autism and neurodegeneration. Our data will also directly impact current theories and models of homeostatic signaling. Current theoretical models have captured widespread interest. Molecular insight will provide important new ideas and new constraints for the next generation of theoretical models of homeostatic plasticity, learning and memory.