Mechanisms and Functions of Synapses and Circuits

项目摘要 这项资助的最终目标是确定突触和回路如何在体内发挥作用来控制行为。 一个主要的焦点是阐明短期可塑性的机制，并了解功能和 不同突触的短期可塑性的行为作用。虽然突触可塑性在 在整个大脑中，功能障碍与许多神经系统疾病有关， 可塑性的相互作用形式仍然知之甚少。我们将重点讨论一个假设， 钙传感器响应突触前钙信号以增强神经递质释放。我们的研究结果 提示易化和强直后增强（PTP）使用2种不同类型钙感受器来增强 在不同的时间尺度上传输。易化是突触增强的一种形式，持续数百年。 毫秒我们已经发现易化是由突触结合蛋白7（syt 7）介导的，syt 7是一种钙离子通道， 具有缓慢动力学的敏感同种型。在初步的研究中，我们发现在syt 7基因敲除小鼠中，易化作用是 即使释放的初始概率和突触前钙信号没有改变，也会被消除。病毒 SYT 7的表达恢复SYT 7敲除动物中的易化。这些研究表明，我们已经确定， 长期以来一直寻求钙传感器的促进作用。未来的研究将阐明syt 7在促进 导致不同的行为。PTP是一种突触增强的形式，持续数十秒， 突触前神经元的高频率放电。我们最近发现PKCβ是一种钙离子通道， 在Held的花萼处有PTP的传感器。我们会继续厘清私人参建居屋的机制，并计划最终 使用分子遗传学从特定突触中选择性地消除PTP，以确定PTP在 不同的行为 第二个主要的焦点是澄清小脑电路和了解不同的电路元件如何发挥作用 小脑功能，调节运动学习，感觉运动整合和社会行为。我们有 最近发现，所有浦肯野细胞（PC）都有针对小脑内多种类型细胞的侧枝， 皮质，即使是成年人。这表明有必要考虑从PC的输出到 小脑皮质我们将确定PC-PC突触是否促进同步活动， 假设突触连接的PC会聚到同一个DCN神经元上并调节其放电。 这些研究将扩展我们对小脑处理的理解，并将提供重要的见解， 由小脑功能障碍引起的神经系统疾病。我们还将确定特定区域的 小脑皮质调节特定行为。

Project Summary The ultimate goal of this grant is to determine how synapses and circuits function in vivo to control behaviors. One major focus is to clarify the mechanisms of short-term plasticity, and to understand the functional and behavioral role of short term plasticity at different synapses. Although synaptic plasticity plays a crucial role throughout the brain, and dysfunction has been implicated in numerous neurological disorders, the many interacting forms of plasticity remain poorly understood. We will focus on the hypothesis that specialized calcium sensors respond to presynaptic calcium signals to enhance neurotransmitter release. Our findings suggest that facilitation and posttetanic potentiation (PTP) use 2 different types of calcium sensors to enhance transmission on different time scales. Facilitation is a form of synaptic enhancement that lasts for hundreds of milliseconds. We have found that facilitation is mediated by synaptotagmin 7 (syt7), which is a calcium- sensitive isoform with slow kinetics. In preliminary studies we find that in syt7 knockout mice, facilitation is eliminated even though the initial probability of release and presynaptic calcium signals are unaltered. Viral expression of syt7 restores facilitation in syt7 knockout animals. These studies indicate that we have identified the long sought after calcium sensor for facilitation. Future studies will clarify the role of syt7 in facilitation in contributing to different behaviors. PTP is a form of synaptic enhancement lasting for tens of seconds following a period of high-frequency firing of presynaptic neurons. We have recently shown that PKCβ is a calcium sensor for PTP at the calyx of Held. We will continue to clarify the mechanism of PTP and ultimately plan to use molecular genetics to selectively eliminate PTP from specific synapses to determine the role of PTP in different behaviors. A second major focus is to clarify cerebellar circuitry and understand how different circuit elements contribute to cerebellar function, which regulates motor learning, sensorimotor integration and social behaviors. We have recently shown that all Purkinje cells (PCs) have collaterals that target many types of cells within the cerebellar cortex, even in adults. This indicates it is necessary to consider feedback from the output of PCs to the cerebellar cortex. We will determine if PCPC synapses promote synchronous activity also test the hypothesis that synaptically-connected PCs converge onto the same DCN neuron and regulate its firing. These studies will extend our understanding of cerebellar processing and will provide important insights into neurological disorders that arise from cerebellar dysfunction. We will also determine how specific regions of the cerebellar cortex regulate specific behaviors.