Local Homeostatic Control of Synapse Function

突触功能的局部稳态控制

• 批准号: 8054257
• 负责人: Michael Mark Alexander Sutton
• 金额: $ 37.27万
• 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/8054257
• 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着信息处理能力源于他们接收到的突触连接的密集网络以及这些突触的能力随经验而改变。但是，被认为是学习和记忆基础的突触变化星座（“ Hebbian”可塑性）也可以在神经回路内产生不稳定的活动，从而导致从智力低下到癫痫病的潜在衰弱的结果。过去十年中的工作表明，突触可塑性的“体内稳态”形式可以通过补偿性增加或降低突触强度来抵消潜在的突触活动水平，从而促进神经元网络内的长期稳定性。尽管这个想法对该领域产生了广泛的兴趣，但我们仍然缺乏清楚地了解这些补偿性变化是如何在突触中实施的，以及它们如何与Hebbian Synaptic修改一起工作。最近的工作挑战了初始记录所提供的图片，即中央突触的稳态补偿是一种本质缓慢且范围内的可塑性形式。现在，我们提出了这样一个假设，即稳态突触可塑性不是由整体的全球过程定义的，而是描述了一个补偿机制的家族，其中的子集在突触时与信息存储很重要的过程在本地相互作用。通过检查突触/神经元活动的独特特征是否可以驱动突触补偿的不同形式（AIM 1），将在三个特定目标中进行检验（AIM 1）；神经元中的分隔生化加工是否介导稳态可塑性的不同方面（AIM 2）；以及稳态补偿的局部机制是否在同一组突触输入中与Hebbian突触可塑性相互作用（AIM 3）。由于该项目围绕着基本神经元功能至关重要的一类过程，因此其含义可能会广泛，为神经元信号传导，发育以及与稳态可塑性（例如癫痫病）联系起来的神经元信号，发育和毁灭性神经系统疾病的方面。该项目还将为与我们对学习和记忆的理解有关的许多基本科学问题提供信息，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突触修饰如何在面对否则会逆转它们的补偿机制的情况下忍受。 公共卫生相关性：我们的学习和记忆能力被认为涉及大脑突触连接网络中的特定变化；但是，被认为是学习和记忆基础的突触变化也会在神经回路内产生不稳定的活动性，从而导致一系列令人衰弱的结果，从智力低下到癫痫病。过去十年中的工作表明，不同类别的突触修饰 - 稳态突触可塑性 - 促进突触强度的代偿性变化，以抵消神经元网络中不稳定的活性水平，最近的证据与神经学功能障碍的调节改变了调节的调节。但是，传统的观点是，这些稳态机制是整体上对神经元的作用，而不是在单个突触的层面上作用，因此与对学习和记忆存储重要的机制不相互作用。最近的证据提出了这一观点的挑战，促使我们提出并检验了以下假设：神经元不仅限于单一的全球补偿机制来促进网络稳定性，而可以从机械上赋予的过程的家族中汲取灵感，其中一些过程可以在突触上进行，并且可以与信息处理和存储重要的机制相互作用。