Mechanisms and Functions of Synapses and Circuits

突触和电路的机制和功能

基本信息

批准号：
10066370
负责人：
WADE G REGEHR
金额：
$ 92.48万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2024-11-30
项目状态：
已结题

项目摘要

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.

项目概要这笔资助的最终目标是确定突触和电路如何在体内发挥作用来控制行为。一个主要焦点是阐明短期可塑性的机制，并了解其功能和作用。尽管突触可塑性起着至关重要的作用，但短期可塑性在不同突触的行为作用。整个大脑的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，我们将重点关注专门化的假设。钙传感器响应突触前钙信号以增强神经递质释放。建议促进和强直后增强（PTP）使用两种不同类型的钙传感器来增强不同时间尺度上的传递是持续数百次的突触增强形式。我们发现促进作用是由突触结合蛋白 7 (syt7) 介导的，它是一种钙- 在初步研究中，我们发现在 syt7 敲除小鼠中，促进作用是缓慢动力学的。即使释放的初始概率和突触前钙信号未改变，病毒也会被消除。 syt7 的表达恢复了 syt7 敲除动物的促进作用。这些研究表明我们已经确定了这一点。长期以来备受追捧的促进钙传感器，未来的研究将阐明 syt7 在促进中的作用。 PTP 是一种持续数十秒的突触增强形式。我们最近证明 PKCβ 是一种钙离子。 Held 花萼上的 PTP 传感器我们将继续阐明 PTP 的机制，并最终计划利用分子遗传学选择性地消除特定突触中的 PTP，以确定 PTP 在不同的行为。第二个主要重点是阐明小脑电路并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。最近表明，所有浦肯野细胞 (PC) 都具有针对小脑内多种类型细胞的侧枝循环皮层，即使是成年人，这表明有必要考虑 PC 输出到大脑的反馈。我们将确定 PCPC 突触是否促进同步活动并测试假设突触连接的 PC 汇聚到同一个 DCN 神经元并调节其放电。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我们还将确定小脑功能障碍引起的神经系统疾病的具体区域。小脑皮质调节特定的行为。