Global synaptic plasticity mechanisms in visual cortex

视觉皮层的整体突触可塑性机制

• 批准号: 8186021
• 负责人: Hey-Kyoung Lee
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8186021
• 关键词: AMPA Receptors; Address; Adult; Appearance; Blindness; Brain; Cells; Cytoskeletal Proteins; Data; Development; Endocytosis; Equilibrium; Event; Excitatory Synapse; Exposure to; Eye; Global Change; Homeostasis; Hour; Immediate-Early Genes; Inhibitory Synapse; Knock-out; Life; Light; Long-Term Depression; Long-Term Potentiation; Maintenance; Metabotropic Glutamate Receptors; Modification; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Optics; Phosphorylation; Play; Process; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Role; Signal Transduction; Site; Slide; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Time; Vision; Visual; Visual Cortex; analytical method; area striata; critical period; dark rearing; experience; hippocampal pyramidal neuron; novel; postnatal; postsynaptic; receptor; relating to nervous system; scale up; sensory cortex; synaptic function; tool; visual deprivation

DESCRIPTION (provided by applicant): Visual experience can produce long-lasting changes in the function of the primary visual cortex (V1), especially during a critical period early in postnatal life. There are two forms of functional plasticity that occur at V1 synapses: one that is input-specific and the other that is global across all synapses. The former is thought to be critical for the formation and/or maintenance of proper connectivity, while the latter provides homeostasis and stability. We found that a few days of binocular visual deprivation (i.e. dark-rearing) following normal development globally increases the strength of excitatory synaptic transmission in the superficial layers of V1, which was rapidly reversed by re-exposure to light. These changes followed the rules of a homeostatic plasticity mechanism termed synaptic scaling. We found that AMPA receptor (AMPAR) regulation plays a central role in the visual experience-induced homeostatic synaptic changes. Specifically, we observed an increase in phosphorylation of AMPAR subunit GluR1 (or GluA1) and appearance of Ca2+permeable AMPARs (CP-AMPARs) at synapses, which correlated with the increase in excitatory synaptic strength observed in dark-reared mice. On the other hand, an immediate early gene product Arc (activity-regulated cytoskeletal protein) was involved in scaling down excitatory synapses with light exposure. Our results provide a molecular framework to understand homeostatic plasticity at excitatory synapses in V1. However, there are several questions that remain unanswered: The molecular events that trigger synaptic scaling, whether inhibitory synapses undergo homeostatic synaptic plasticity, and how synaptic scaling interacts with input-specific plasticity are unknown. We will attempt to investigate these in the current proposal. Because of the central role AMPAR regulation and Arc play in visual experience-induced homeostatic synaptic plasticity, we will examine their upstream signals, specifically signaling through metabotropic glutamate receptors (mGluRs), to determine the molecular events that trigger this form of plasticity (Aim 1). We recently found that a brief dark-rearing triggers global changes in inhibitory synaptic function, which was independent of the mechanisms recruited for excitatory synapse regulation. Hence, we will examine the mechanisms of homeostatic regulation of inhibitory synapses in V1 (Aim 2). Global homeostatic synaptic changes are expected to alter the rules of input-specific synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). In line with this, we found that visual deprivation reveals a novel NMDAR-independent form of synaptic plasticity, which will be investigated in this proposal (Aim 3). Understanding how excitatory and inhibitory synaptic function is globally adjusted by visual experience is critical, because it impacts the rules of input-specific synaptic modification. Our finding that homeostatic synaptic plasticity in the superficial layers of V1 can result from a few days of visual deprivation, even in adults, suggest that elucidating the underlying molecular mechanisms will provide valuable tools to either enhance or restrict plasticity in V1. PUBLIC HEALTH RELEVANCE: Loss of vision early in life causes blindness even if the optics of the eye is restored later, because it permanently changes the function of the brain. Therefore, understanding how the brain function changes by visual experience is critical in developing ways to recover vision.

描述（由申请人提供）：视觉体验可以对初级视觉皮层（V1）的功能产生持久的变化，特别是在出生后早期的关键时期。 V1 突触处发生两种形式的功能可塑性：一种是输入特定的，另一种是所有突触全局的。前者被认为对于形成和/或维持适当的连接至关重要，而后者则提供体内平衡和稳定性。我们发现，正常发育后几天的双眼视觉剥夺（即黑暗饲养）会整体增加 V1 浅层兴奋性突触传递的强度，而通过重新暴露在光线下，这种情况会迅速逆转。这些变化遵循称为突触缩放的稳态可塑性机制的规则。我们发现 AMPA 受体 (AMPAR) 调节在视觉体验诱导的稳态突触变化中起着核心作用。具体来说，我们观察到突触处 AMPAR 亚基 GluR1（或 GluA1）磷酸化的增加和 Ca2+ 可渗透 AMPAR（CP-AMPAR）的出现，这与在黑暗饲养的小鼠中观察到的兴奋性突触强度的增加相关。另一方面，直接早期基因产物 Arc（活性调节细胞骨架蛋白）参与了光照射下兴奋性突触的缩小。我们的结果提供了一个分子框架来理解 V1 兴奋性突触的稳态可塑性。然而，还有几个问题尚未得到解答：触发突触缩放的分子事件、抑制性突触是否经历稳态突触可塑性以及突触缩放如何与输入特异性可塑性相互作用尚不清楚。我们将尝试在当前提案中调查这些内容。由于 AMPAR 调节和 Arc 在视觉体验诱导的稳态突触可塑性中发挥核心作用，我们将检查它们的上游信号，特别是通过代谢型谷氨酸受体 (mGluR) 发出的信号，以确定触发这种形式可塑性的分子事件（目标 1） ）。我们最近发现，短暂的黑暗饲养会引发抑制性突触功能的整体变化，这与兴奋性突触调节所招募的机制无关。因此，我们将研究 V1 中抑制性突触的稳态调节机制（目标 2）。全局稳态突触变化预计会改变输入特异性突触可塑性的规则，例如长时程增强（LTP）和长时程抑制（LTD）。与此相一致，我们发现视觉剥夺揭示了一种新的独立于 NMDAR 的突触可塑性形式，本提案将对此进行研究（目标 3）。了解兴奋性和抑制性突触功能如何通过视觉体验进行全局调整至关重要，因为它会影响输入特异性突触修饰的规则。我们发现，V1 浅层的稳态突触可塑性可能是由几天的视觉剥夺造成的，即使在成年人中也是如此，这表明阐明潜在的分子机制将为增强或限制 V1 可塑性提供有价值的工具。 公众健康相关性：即使后来眼睛的光学功能恢复，生命早期丧失视力也会导致失明，因为它会永久改变大脑的功能。因此，了解视觉体验如何改变大脑功能对于开发恢复视力的方法至关重要。