Homeostatic regulation and trafficking of AMPA receptors at single synapses

描述(申请人提供)：在中枢神经系统中，神经元接受来自许多周围细胞的大量突触输入，单个突触相互独立地发挥作用。突触可塑性是一种在生理条件下发生的突触自主事件，对包括学习和记忆在内的高级大脑功能至关重要。大量数据表明，Hebbian型突触可塑性包括长时程增强(LTP)和长时程抑制(LTD)，以及非Hebbian型稳态突触可塑性都是通过调节突触AMPA受体(AMPAR)的丰度来表达的，通常是通过囊泡介导的受体运输。鉴于可塑性是高度突触特异性的事实，研究突触特异性的、活性依赖的AMPAR表达调控将为我们理解突触生理和脑功能提供重要的见解。此外，动态平衡可塑性仅在神经元群体水平上进行了研究；它是否以及如何在单个突触中表达仍然是难以捉摸的。为了解决这些问题，我们在神经元培养中建立了两个实验范式，其中可识别的单个突触的活动水平受到特定调控。我们将研究AMPAR丰度被特异性调节的细胞机制，以响应单个突触的活性变化。与公共健康相关：该应用程序旨在了解神经元中细胞间通信强度受到调节的机制。通过研究突触特异性的、活性依赖的AMPAR表达调控，本研究将为我们理解突触的生理和脑功能提供重要的见解。

DESCRIPTION (provided by applicant): In the central nervous system, a neuron receives a large number of synaptic inputs from many surrounding cells, with individual synapses acting independently of one another. Synaptic plasticity, which is essential for high brain functions including learning and memory, is a synapse autonomous event under physiological conditions. A large amount of data has shown that both Hebbian-type synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD), as well as non-Hebbian type homeostatic synaptic plasticity are expressed via regulation of synaptic AMPA receptor (AMPAR) abundance, often by vesicle-mediated receptor trafficking. Given the fact that plasticity is highly synapse specific, investigation of synapse specific, activity-dependent regulation of AMPAR expression will provide crucial insights in our understanding of synapse physiology and brain function. Furthermore, homeostatic plasticity has been studied only at the neuronal population level; if and how it is expressed at single synapses remains elusive. To address these issues, we have set up two experimental paradigms in neuronal culture, in which activity levels of identifiable single synapses are specifically regulated. We will investigate the cellular mechanisms by which AMPAR abundance is specifically regulated in response to activity changes at single synapses. PUBLIC HEALTH RELEVANCE: The application aims to understand the mechanisms by which the strength of intercellular communication is regulated in neurons. By investigating synapse specific, activity-dependent regulation of AMPAR expression, this study will provide crucial insights in our understanding of synapse physiology and brain function.