Global synaptic plasticity mechanisms in visual cortex

描述(由申请人提供)：视觉体验对于视觉皮质的正常发育和功能至关重要。例如，在儿童时期延迟摘除白内障超过了关键时期会导致受影响眼睛的功能性失明。动物研究表明，这种功能中断是由于视觉皮质连接性的变化造成的。因此，要理解依赖视觉经验的可塑性，就需要阐明突触修饰的皮质机制。 在视觉皮质中，有两种已知的突触修饰机制。一种机制是通过改变特定突触的连接性，如长期增强(LTP)和长期抑制(LTD)。另一种影响细胞内全局的突触强度。这种全球可塑性发生在较慢的时间尺度上，并被认为是一种稳定神经网络的负反馈机制。突触特异性可塑性背后的细胞机制受到了极大的关注。然而，人们对全球可塑性的机制知之甚少。我们发现，在黑暗中饲养动物会增加AMPA受体介导的突触反应的大小，这与最近一项视觉剥夺研究的结果类似。这些结果表明，慢性视觉剥夺可在体内整体上调兴奋性突触强度。此外，我们还发现暗饲养增加了AMPA受体在特定部位的磷酸化。在这项建议中，我们打算研究AMPA受体磷酸化在全球突触可塑性中的作用。这项拟议研究的结果将为视觉体验如何在全球范围内在分子水平上改变突触强度提供见解。从我们的工作中获得的知识可以被概括出来，以进一步理解神经回路是如何通过发育过程中的活动和经验来塑造的。

DESCRIPTION (provided by applicant): Visual experience is critical for proper development and function of the visual cortex. For example, delayed removal of cataracts beyond a critical period in childhood results in functional blindness of the affected eye. Animal studies have shown that this functional disconnection results from changes in connectivity of the visual cortex. Therefore, understanding visual experience-dependent plasticity requires elucidation of cortical mechanisms of synaptic modification. There are two identified mechanisms of synaptic modification in the visual cortex. One type of mechanism is by altering connectivity at specific synapses, such as long-term potentiation (LTP) and long-term depression (LTD). The other affects synaptic strengths globally within a cell. This type of global plasticity occurs on a slower time scale, and has been implicated in acting as a negative feedback mechanism that stabilizes neural networks. The cellular mechanisms that underlie synapse-specific plasticity have received much attention. However, relatively little is known regarding the mechanisms of global plasticity. We found that rearing animals in the dark increases the size of AMPA receptor-mediated synaptic responses, similar to the results from a recent visual deprivation study. These results indicate that chronic visual deprivation can globally up-regulate excitatory synaptic strength in vivo. In addition, we found that dark rearing increases phosphorylation of AMPA receptors at specific sites. In this proposal, we intend to investigate the involvement of AMPA receptor phosphorylation in global synaptic plasticity. The results from the proposed study will provide insights into how visual experience acts globally to change synaptic strength at a molecular level. The knowledge gained from our work can be generalized to further our understanding of how neural circuits are sculpted by activity during development and by experience.