Global synaptic plasticity mechanisms in visual cortex

描述（由申请人提供）：视觉体验可以产生初级视觉皮层（V1）功能的长期变化，特别是在出生后生命早期的关键时期。V1突触有两种形式的功能可塑性：一种是特定于输入的，另一种是遍及所有突触的。前者被认为是形成和/或维持适当连通性的关键，而后者提供稳态和稳定性。我们发现，在正常发育后的几天内，双眼视觉剥夺（即黑暗饲养）会增加V1浅层兴奋性突触传递的强度，这种情况会通过再次暴露于光下而迅速逆转。这些变化遵循一种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）调控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AMPAR亚基GluR1（或GluA1）磷酸化的增加以及突触中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有关。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。我们的研究结果为理解V1兴奋性突触的稳态可塑性提供了一个分子框架。然而，有几个问题仍未得到解答：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。我们将在当前的提案中尝试研究这些问题。由于AMPAR调控和Arc在视觉体验诱导的稳态突触可塑性中发挥核心作用，我们将研究它们的上游信号，特别是通过代谢谷氨酸受体（mGluRs）发出的信号，以确定触发这种可塑性形式的分子事件（Aim 1）。我们最近发现，一个短暂的黑暗饲养触发抑制突触功能的全局变化，这是独立于兴奋性突触调节的机制。因此，我们将研究V1中抑制性突触的稳态调节机制（目的2）。整体内稳态突触变化有望改变输入特异性突触可塑性的规则，如长期增强（LTP）和长期抑制（LTD）。与此相一致，我们发现视觉剥夺揭示了一种新的与nmdar无关的突触可塑性形式，这将在本提案中进行研究（Aim 3）。理解兴奋性和抑制性突触功能是如何被视觉经验全局调节的是至关重要的，因为它影响了输入特异性突触修饰的规则。我们发现，即使在成人中，几天的视觉剥夺也可能导致V1浅层的稳态突触可塑性，这表明阐明潜在的分子机制将为增强或限制V1的可塑性提供有价值的工具。

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.