Local Homeostatic Control of Synapse Function

突触功能的局部稳态控制

• 批准号: 8423049
• 负责人: Michael Mark Alexander Sutton
• 金额: $ 35.74万
• 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/8423049
• 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.

描述(申请人提供)：哺乳动物大脑中神经元非凡的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星座(“Hebbian”可塑性)也可以产生神经回路内活动的不稳定，导致从智力低下到癫痫的一系列潜在的衰弱结果。过去十年的工作表明，“稳态”形式的突触可塑性可以通过补偿性增加或减少突触强度来抵消潜在的不稳定突触活动水平，从而促进神经元网络中的长期稳定。虽然这一想法引起了该领域的广泛兴趣，但我们仍然缺乏关于这些代偿性变化是如何在突触上实施的，以及它们如何与Hebbian突触修饰协同工作的清晰图景。最近的工作挑战了最初的描述，即中央突触的动态平衡补偿是一种固有的缓慢和细胞范围的可塑性形式。我们现在提出的假设是，稳态突触可塑性不是由一个单一的全球过程定义的，而是描述了一系列补偿机制，其中一部分在突触局部与信息存储重要的过程相互作用。这一假说将通过三个具体的目标进行检验：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(目标1)；神经元中的区隔生化处理是否调节不同方面的稳态可塑性(目标2)；以及局部的稳态补偿机制是否与同一组突触输入的Hebbian突触可塑性相互作用(目标3)。由于这个项目围绕着一类对基本神经元功能至关重要的过程，它的影响可能会广泛地向神经元信号传递、发育以及与自身平衡可塑性有关的破坏性神经障碍(如癫痫)提供信息。该项目还将为许多与我们对学习和记忆的理解有关的基础科学问题提供信息，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突触修改如何在面对原本会逆转它们的代偿机制时持续下去。