Local Homeostatic Control of Synapse Function

描述（由申请人提供）：哺乳动物大脑中神经元的显著信息处理能力源于它们接收的突触连接的密集网络以及这些突触随经验变化的能力。然而，被认为是学习和记忆基础的突触变化（“赫布”可塑性）也会在神经回路内产生活动的不稳定性，导致从智力迟钝到癫痫的潜在的一系列衰弱性结果。过去十年的研究表明，突触可塑性的“稳态”形式可以通过补偿突触强度的增加或减少来抵消潜在的不稳定水平的突触活动，从而促进神经元网络内的长期稳定性。虽然这一想法在该领域引起了广泛的兴趣，但我们仍然缺乏一个清晰的画面，这些补偿性变化是如何在突触上实现的，以及它们如何与赫布突触修饰协同工作。最近的研究已经挑战了最初的说法，即中央突触的稳态补偿是一种本质上缓慢的、细胞范围内的可塑性形式。我们现在提出的假设，稳态突触可塑性不是由一个单一的全球过程，而是描述了一个家庭的补偿机制，其中一个子集的相互作用，在突触与信息存储重要的过程。这一假设将在三个特定的目标进行测试，通过检查：突触/神经元活动的独特功能是否驱动不同形式的突触补偿（目标1）;神经元中的区室化生化处理是否介导稳态可塑性的不同方面（目标2）;以及稳态补偿的局部机制是否与Hebbian突触可塑性在同一组突触输入中相互作用（目标3）。由于该项目围绕着一类对基本神经元功能至关重要的过程，因此其影响可能很广泛，为神经元信号传导，发育以及与稳态可塑性有关的破坏性神经系统疾病（如癫痫）提供信息。该项目还将告知与我们对学习和记忆的理解相关的许多基础科学问题，例如局部蛋白质合成和降解在突触可塑性中的作用，以及这种赫布突触修饰如何在面对补偿机制时能够忍受，否则会逆转它们。

DESCRIPTION (provided by applicant): The remarkable information processing capacity of neurons in the mammalian brain stems from the dense network of synaptic connections they receive and the ability of these synapses to change with experience. However, the constellation of synaptic changes thought to underlie learning and memory ("Hebbian" plasticity) can also produce instability of activity within neural circuits, leading to a potential host of debilitating outcomes ranging from mental retardation to epilepsy. Work over the last decade has suggested that "homeostatic" forms of synaptic plasticity can promote long-term stability within neuronal networks by offsetting potentially destabilizing levels of synaptic activity through compensatory increases or decreases in synaptic strength. While this idea has generated wide interest in the field, we still lack a clear picture of how these compensatory changes are implemented at synapses and how they work in concert with Hebbian synaptic modifications. Recent work has challenged the picture provided by initial accounts that homeostatic compensation at central synapses as an intrinsically slow and cell-wide form of plasticity. We now propose the hypothesis that homeostatic synaptic plasticity is not defined by a unitary global process, but rather describes a family of compensatory mechanisms, a subset of which interact locally at synapses with processes important for information storage. This hypothesis will be tested in three specific aims, by examining: whether unique features of synaptic/neuronal activity drive distinct forms of synaptic compensation (Aim 1); whether compartmentalized biochemical processing in neurons mediates distinct aspects of homeostatic plasticity (Aim 2); and whether local mechanisms of homeostatic compensation interact with Hebbian synaptic plasticity at the same set of synaptic inputs (Aim 3). Since this project centers around a class of processes that are fundamental to basic neuron function, its implications are likely to broad, informing aspects of neuron signaling, development, and the devastating neurological disorders that have been linked with homeostatic plasticity, such as epilepsy. This project will also inform many basic science issues related to our understanding of learning and memory, such as the role of localized protein synthesis and degradation in synaptic plasticity and how such Hebbian synaptic modifications can endure in the face of compensatory mechanisms that would otherwise reverse them.