Local Homeostatic Control of Synapse Function

突触功能的局部稳态控制

• 批准号: 8212229
• 负责人: Michael Mark Alexander Sutton
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212229
• 关键词: Accounting; Action Potentials; Acute; Address; Aging; Alzheimer' s Disease; Autistic Disorder; Basic Science; Biochemical Process; Brain; Brain Stem; Cells; Development; Epilepsy; Event; Exhibits; Family; Financial compensation; Goals; Hippocampus (Brain); Individual; Information Storage; Learning; Life; Link; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Mental Retardation; Modification; Molecular; Neuraxis; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Outcome; Perfusion; Play; Presynaptic Terminals; Process; Protein Biosynthesis; Published Comment; Regulation; Role; Signal Transduction; Slice; Synapses; Synaptic plasticity; Testing; Translations; Work; base; experience; hippocampal pyramidal neuron; information processing; inhibitor/antagonist; interest; knock-down; long term memory; memory encoding; memory process; multicatalytic endopeptidase complex; nervous system disorder; neural circuit; neurotransmission; postsynaptic; presynaptic; protein degradation; public health relevance; repaired; response; synaptic function; synthetic protein

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. PUBLIC HEALTH RELEVANCE: Our ability to learn and remember is thought to involve specific changes in the network of synaptic connections in the brain; however, synaptic changes thought to underlie learning and memory can also produce instability of activity within neural circuits, leading to a host of debilitating outcomes ranging from mental retardation to epilepsy. Work over the last decade has suggested that a different class of synaptic modification - homeostatic synaptic plasticity - promotes compensatory changes in the strength of synapses to offset destabilizing levels of activity within neuronal networks and recent evidence has linked altered regulation of homeostatic plasticity with neurological dysfunction. However, the traditional viewpoint has been that these homeostatic mechanisms act on the neuron as a whole, rather than at the level of individual synapses, and therefore do not interact with mechanisms important for learning and memory storage. Recent evidence has challenged this view prompting us to propose and test the hypothesis that neurons are not limited to a single global compensation mechanism to promote network stability, but can rather draw from a family of mechanistically-distinct processes, some of which act locally at synapses and can interact with mechanisms important for information processing and storage.

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密集突触连接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集群（“Hebbian”可塑性）也可以在神经回路中产生活动不稳定，导致从智力迟钝到癫痫等一系列潜在的衰弱结果。过去十年的研究表明，“内稳态”形式的突触可塑性可以通过代偿性突触强度的增加或减少来抵消突触活动的潜在不稳定水平，从而促进神经网络的长期稳定。虽然这一想法在该领域引起了广泛的兴趣，但我们仍然缺乏关于这些代偿性变化如何在突触中实现以及它们如何与Hebbian突触修饰协同工作的清晰图景。最近的研究挑战了最初的说法，即中枢突触的稳态补偿本质上是一种缓慢的、全细胞范围的可塑性形式。我们现在提出这样一个假设，即稳态突触可塑性不是由一个单一的全局过程定义的，而是描述了一系列补偿机制，其中一个子集在突触局部与信息存储重要过程相互作用。这一假设将在三个具体目标中进行测试，通过检查：突触/神经元活动的独特特征是否驱动不同形式的突触补偿（目的1）；神经元的区隔化生化处理是否介导了稳态可塑性的不同方面（目的2）；以及在同一组突触输入下，局部稳态补偿机制是否与Hebbian突触可塑性相互作用（目的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展开，因此其影响可能很广泛，可以为神经元信号传导、发育以及与稳态可塑性相关的毁灭性神经系统疾病（如癫痫）提供信息。该项目还将告知许多与我们对学习和记忆的理解相关的基础科学问题，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Hebbian突触修饰如何在面对补偿机制时能够持续下去，否则会逆转它们。