Global synaptic plasticity mechanisms in visual cortex

描述（由申请人提供）：视觉体验可以在初级视觉皮层（V1）的功能中产生持久的变化，特别是在出生后早期的关键时期。V1突触有两种形式的功能可塑性：一种是输入特异性的，另一种是全局性的。前者被认为是形成和/或维持适当连接的关键，而后者提供稳态和稳定性。我们发现，几天的双眼视觉剥夺（即黑暗饲养）以下的正常发展，全球增加了兴奋性突触传递的V1，这是迅速逆转的浅层重新暴露于光的强度。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发挥着核心作用。具体而言，我们观察到AMPAR亚基GluR 1（或GluA 1）磷酸化的增加和突触处Ca 2+渗透性AMPAR（CP-AMPAR）的出现，这与在黑暗饲养小鼠中观察到的兴奋性突触强度的增加相关。另一方面，立即早期基因产物Arc（活性调节的细胞骨架蛋白）参与缩小兴奋性突触与光暴露。我们的研究结果提供了一个分子框架，以了解稳态可塑性兴奋性突触V1。然而，有几个问题仍然没有答案：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。我们将在目前的提案中尝试调查这些问题。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的核心作用，我们将研究其上游信号，特别是通过代谢型谷氨酸受体（mGluRs）的信号传导，以确定触发这种形式的可塑性的分子事件（目的1）。我们最近发现，短暂的黑暗饲养触发抑制性突触功能的全球变化，这是独立的兴奋性突触调节招募的机制。因此，我们将研究V1抑制性突触的稳态调节机制（目的2）。整体稳态突触变化有望改变输入特异性突触可塑性的规则，如长时程增强（LTP）和长时程抑制（LTD）。与此一致，我们发现视觉剥夺揭示了一种新的NMDAR独立形式的突触可塑性，这将在本提案中进行研究（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是至关重要的，因为它影响了输入特定突触修饰的规则。我们的发现，稳态突触可塑性在V1的浅层可以导致几天的视觉剥夺，即使在成年人中，表明阐明潜在的分子机制将提供有价值的工具，无论是增强或限制可塑性V1。

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.