Rab3A-Mediated Regulation of Quantal Size after Loss of Activity

项目4 每年有近10万人因创伤性脑损伤或脊髓损伤而终身残疾。 今天，有500多万永久性残疾人活着。神经科学研究的一个主要目标是 了解并促进神经系统损伤后恢复的机制。脑干神经元反应 或者试图弥补伤害。不幸的是，即使是恢复机制， 产生意想不到的后果，如脊髓损伤后的痉挛，或皮层损伤后的癫痫。 脑损伤这些异常行为是由于单个神经元功能的变化造成的。突触 传递，信号从一个神经元到下一个神经元的通信，异常增加或 降低损伤后突触传递的变化可能通过正常的突触传递机制发生。 可塑性是学习新任务或掌握外语的基础。或者，它们可能涉及 完全独特的机制。我们的目标是确定损伤诱导的可塑性的细胞机制 突触传递在脊髓或大脑的复杂环境中，这是一项艰巨的任务， 成千上万的神经元相互之间形成了数百万个突触。我们把问题简化为 损伤对一个突触的影响，运动神经元和肌肉之间的突触， 神经肌肉接头为了模拟损伤的影响，我们用 河豚毒素，河豚的毒素，可以通过麻痹横膈膜来杀死人。我们的数据表明 突触囊泡蛋白RabSA对于损伤诱导的可塑性是必需的。为了验证这个假设，我们将 确定损伤诱导的可塑性如何在RabSA功能受损的突变小鼠中改变。的 这项建议的研究将大大促进我们对神经系统对长时间睡眠的反应的理解。 受伤后活动的长期变化。这些知识对于防止长期 残疾。

Project 4 Every year almost 100,000 people suffer permanent disability from a traumatic brain or spinal cord injury. Over 5 million people with permanent disability are alive today. A major goal of neuroscience research is to understand and promote mechanisms that allow recovery after nervous system injury. Spared neurons react adversely to the injury, or try to compensate for the injury. Unfortunately, even recovery mechanisms can produce unintended consequences, such as spasticity after spinal cord injury, or epilepsy after a cortical brain injury. These anomalous behaviors are due to changes in the functions of individual neurons. Synaptic transmission, the communication of a signal from one neuron to the next, is abnormally increased or decreased. The changes in synaptic transmission after injury may occur through mechanisms of normal plasticity that underlie learning a new task or acquiring a foreign language. Alternatively, they may involve completely unique mechanisms. Our goal is to determine the cellular mechanisms of injury-induced plasticity of synaptic transmission. This is a Herculean task in the complex environment of the spinal cord or brain, where thousands of neurons make millions of synapses with each other. We simplify the problem by looking at the effects of injury on one synapse, the synapse between the motor neuron and the muscle, the neuromuscular junction. To mimic the effects of injury, we block all activity at the neuromuscular junction with tetrodotoxin, the toxin of puffer fish that can kill a person by paralyzing the diaphragm. Our data suggest that the synaptic vesicle protein RabSA is essential for injury-induced plasticity. To test this hypothesis, we will determine how injury-induced plasticity is altered in a mutant mouse with impaired RabSA function. The studies in this proposal will significantly advance our understanding of the nervous system's response to long term changes in activity that occur after injury. Such knowledge is essential in the fight to prevent long term disabilities.