MECHANISMS OF VISUAL PLASTICITY

视觉可塑性的机制

• 批准号: 2888523
• 负责人: Ary S Ramoa
• 金额: $ 15.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2888523
• 关键词: NMDA receptors; amblyopia; antisense nucleic acid; early embryonic stage; electrophysiology; ferrets; gel electrophoresis; immunocytochemistry; molecular cloning; neural plasticity; neural transmission; polymerase chain reaction; receptor expression; receptor sensitivity; synapses; vision disorders; visual cortex; voltage /patch clamp

The mammalian visual system requires experience to develop normally. Lack of sensory experience due to degradation of the visual input of one eye during development may lead to irreversible loss of visual function mediated by this eye. This condition, known as amblyopia, is a major cause of visual disability in children. There is no doubt regarding the substantial scientific and clinical relevance of this type of neural plasticity. However, the cellular and molecular mechanisms underlying this crucial developmental process remain unknown. In recent years much attention has been focused on the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor because of its proposed role in brain development, learning and memory. Its specific role in visual plasticity has, nevertheless, remained elusive. Recent molecular studies have provided an exciting new opportunity to examine the contribution of the NMDA receptor to visual function and plasticity. These studies have shown that this receptor is composed of different subunit proteins and that different combinations of subunits exhibit distinct functional properties. It is proposed here that developmental changes in subunit composition of the NMDA receptor play a critical role in visual plasticity. A novel approach is proposed to examine this hypothesis. Intracortical infusion of antisense DNA will be used to suppress selected NMDA receptor subunits. The receptors should then be assembled from the remaining subunits. The resultant modifications in functional properties of cortical NMDA receptors will be examined by intracellular recordings in cortical slices maintained living in vitro and the changes in visual responses will be assessed in normal animals as well as in those which were monocularly deprived of vision during antisense treatment. This approach offers several significant advantages over currently used pharmacological procedures, such as the possibility of selectively manipulating individual subunits. Moreover, transgenic animals cannot be used to conduct these experiments, since animals lacking some NMDA receptor subunits are not viable. The results should delineate links between the molecular composition of the NMDA receptor and its functional role in visual cortex. In addition, since molecular interventions may one day be used for therapeutic purposes in visual disorders, these studies may provide a new dimension to our clinical armamentarium at the level of the synapse.

哺乳动物视觉系统需要正常发展的经验。 由于一个人的视觉输入退化，缺乏感官体验 开发过程中的眼睛可能导致视觉功能的不可逆转丧失 由这只眼睛介导。 这种情况被称为弱视，是主要的 儿童视觉障碍的原因。 毫无疑问 这种神经的实质科学和临床相关性 可塑性。 但是，细胞和分子机制 这个关键的发展过程仍然未知。 近年来 注意力集中在N-甲基-D-天冬氨酸（NMDA）亚型上 兴奋性氨基酸受体的拟议作用 发展，学习和记忆。 它在视觉中的特定作用 但是，可塑性仍然难以捉摸。 最近的分子 研究为研究 NMDA受体对视觉功能和可塑性的贡献。 这些研究表明，该受体由不同的 亚基蛋白和亚基的不同组合表现出 不同的功能特性。 在这里提出了发展 NMDA受体的亚基组成的变化起着至关重要的作用 在视觉可塑性中。 提出了一种新颖的方法来检查这一点 假设。 反义DNA的心脏内输注将用于 抑制选定的NMDA受体亚基。 然后应该是 从其余亚基组装。 结果修改 皮质NMDA受体的功能特性将通过 皮质切片中的细胞内记录保持体外生活 并且将在正常动物中评估视觉反应的变化 以及在那些单眼剥夺了视力的中 反义治疗。 这种方法提供了几种重要的 优于当前使用的药理学程序，例如 选择性操纵单个亚基的可能性。 而且， 转基因动物不能用于进行这些实验，因为 缺乏某些NMDA受体亚基的动物是不可行的。结果 应该描述NMDA的分子组成之间的链接 受体及其在视觉皮层中的功能作用。 此外，自从 分子干预措施可能有一天用于治疗目的 视觉障碍，这些研究可能为我们的新维度提供了一个新的维度 突触水平的临床武术。